Gene Summary

Gene:PRDM2; PR domain containing 2, with ZNF domain
Summary:This tumor suppressor gene is a member of a nuclear histone/protein methyltransferase superfamily. It encodes a zinc finger protein that can bind to retinoblastoma protein, estrogen receptor, and the TPA-responsive element (MTE) of the heme-oxygenase-1 gene. Although the functions of this protein have not been fully characterized, it may (1) play a role in transcriptional regulation during neuronal differentiation and pathogenesis of retinoblastoma, (2) act as a transcriptional activator of the heme-oxygenase-1 gene, and (3) be a specific effector of estrogen action. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:PR domain zinc finger protein 2
Source:NCBIAccessed: 17 August, 2015


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Breast Cancer
  • Mutation
  • Tumor Suppressor Proteins
  • Neoplastic Cell Transformation
  • RB1
  • Promoter Regions
  • Tumor Markers
  • PRDM2
  • Neoplasm Proteins
  • Messenger RNA
  • Nuclear Proteins
  • Colorectal Cancer
  • Protein Structure, Tertiary
  • DNA Mutational Analysis
  • Frameshift Mutation
  • Apoptosis
  • Chromosome 1
  • Transcription Factors
  • Cancer DNA
  • Gene Silencing
  • Alleles
  • Loss of Heterozygosity
  • Microsatellite Repeats
  • Liver Cancer
  • Tumor Suppressor Gene
  • Gene Expression Profiling
  • Molecular Sequence Data
  • Azacitidine
  • Chromosome Mapping
  • DNA-Binding Proteins
  • DNA Methylation
  • Polymerase Chain Reaction
  • Hepatocellular Carcinoma
  • Cell Proliferation
  • Base Sequence
  • Cancer Gene Expression Regulation
  • Adolescents
  • Histone-Lysine N-Methyltransferase
  • Epigenetics
Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PRDM2 (cancer-related)

Snellenberg S, Cillessen SA, Van Criekinge W, et al.
Methylation-mediated repression of PRDM14 contributes to apoptosis evasion in HPV-positive cancers.
Carcinogenesis. 2014; 35(11):2611-8 [PubMed] Related Publications
Promoter methylation of the transcription factor PRDM14 (PRDI-BF1 and RIZ domain containing 14) represents a highly frequent event in human papillomavirus (HPV)-induced cervical cancers and cancer precursor lesions. Here, we aimed to assess the functional consequences of PRDM14 promoter methylation in HPV-induced carcinogenesis. PRDM14 promoter methylation, expression and consequences of ectopic PRDM14 expression were studied in HPV16-positive cervical and oral cancer cell lines (SiHa, CaSki and 93VU147T), human embryonic kidney 293 (HEK293T) cells and primary human foreskin keratinocytes (HFK). PRDM14 mRNA expression was restricted to HEK293T and HFK cells, and could be upregulated in SiHa cells upon DNA methylation inhibition. Ectopic expression of PRDM14 in SiHa, CaSki and 93VU147T cells resulted in significantly more apoptotic cells, as measured by annexin V labelling, compared to HEK293T and HFK cells. MRNA profiling of 41 apoptosis regulators identified NOXA and PUMA as candidate target genes involved in PRDM14-mediated apoptosis induction. Full-length PRDM14 transactivated both NOXA and PUMA promoters. Transactivation was abolished upon deletion of the PRDM14 DNA binding domain. This suggests that NOXA and PUMA expression is directly regulated by PRDM14, which in case of NOXA was linked to a consensus PRDM14 binding motif in the promoter region. Taken together, these results suggest that PRDM14 acts as a regulator of NOXA and PUMA-mediated apoptosis induction, thereby providing evidence for a tumour suppressive role in HPV-induced carcinogenesis. The contribution of methylation-mediated gene silencing of PRDM14 to apoptosis evasion in HPV-positive cancer cells offers novel therapeutic options for HPV-induced cancers.

Tan SX, Hu RC, Liu JJ, et al.
Methylation of PRDM2, PRDM5 and PRDM16 genes in lung cancer cells.
Int J Clin Exp Pathol. 2014; 7(5):2305-11 [PubMed] Free Access to Full Article Related Publications
AIMS: To investigate the changes of expression and methylation status of PRDM2, PRDM5, PRDM16 in lung cancer cells after treatment with demethylation agent.
METHODS: A549 (lung adenocarcinoma cell line), HTB-182 (lung squamous cell carcinoma cell line) and HBE (normal bronchial cell line) were treated with 5-aza-2dC. The methylation state of PRDM2, PRDM5, PRDM16 was detected by MSP. The expression of PRDM2, PRDM5, PRDM16 was detected by RT-PCR and Western blot analysis. Cell growth was detected by MTT assay.
RESULTS: 5-aza-2-dC reduced the methylation of PRDM2, PRDM5, PRDM16 gene in A549 and HTB-182 cells but not in HBE cells. Consistently, 5-aza-2dC increased mRNA and protein expression of PRDM2, PRDM5, PRDM16 in A549 and HTB-182 cells but not in HBE cells. Furthermore, 5-aza-2dC inhibited the growth of A549 and HTB-182 cells but not HBE cells.
CONCLUSIONS: PRDM2, PRDM5, PRDM16 promoters are methylated and their expression is suppressed in lung cancer cells. Demethylation drug 5-aza-2dC could upregulate the expression of PRDM2, PRDM5, PRDM16 and suppress lung cancer cell growth. 5-aza-2dC has potential to be used for lung cancer therapy by epigenetic mechanism.

Mouradov D, Sloggett C, Jorissen RN, et al.
Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer.
Cancer Res. 2014; 74(12):3238-47 [PubMed] Related Publications
Human colorectal cancer cell lines are used widely to investigate tumor biology, experimental therapy, and biomarkers. However, to what extent these established cell lines represent and maintain the genetic diversity of primary cancers is uncertain. In this study, we profiled 70 colorectal cancer cell lines for mutations and DNA copy number by whole-exome sequencing and SNP microarray analyses, respectively. Gene expression was defined using RNA-Seq. Cell line data were compared with those published for primary colorectal cancers in The Cancer Genome Atlas. Notably, we found that exome mutation and DNA copy-number spectra in colorectal cancer cell lines closely resembled those seen in primary colorectal tumors. Similarities included the presence of two hypermutation phenotypes, as defined by signatures for defective DNA mismatch repair and DNA polymerase ε proofreading deficiency, along with concordant mutation profiles in the broadly altered WNT, MAPK, PI3K, TGFβ, and p53 pathways. Furthermore, we documented mutations enriched in genes involved in chromatin remodeling (ARID1A, CHD6, and SRCAP) and histone methylation or acetylation (ASH1L, EP300, EP400, MLL2, MLL3, PRDM2, and TRRAP). Chromosomal instability was prevalent in nonhypermutated cases, with similar patterns of chromosomal gains and losses. Although paired cell lines derived from the same tumor exhibited considerable mutation and DNA copy-number differences, in silico simulations suggest that these differences mainly reflected a preexisting heterogeneity in the tumor cells. In conclusion, our results establish that human colorectal cancer lines are representative of the main subtypes of primary tumors at the genomic level, further validating their utility as tools to investigate colorectal cancer biology and drug responses.

Chen N, Sato D, Saiki Y, et al.
S100A4 is frequently overexpressed in lung cancer cells and promotes cell growth and cell motility.
Biochem Biophys Res Commun. 2014; 447(3):459-64 [PubMed] Related Publications
S100A4, a small calcium-binding protein belonging to the S100 protein family, is commonly overexpressed in a variety of tumor types and is widely accepted to associate with metastasis by regulating the motility and invasiveness of cancer cells. However, its biological role in lung carcinogenesis is largely unknown. In this study, we found that S100A4 was frequently overexpressed in lung cancer cells, irrespective of histological subtype. Then we performed knockdown and forced expression of S100A4 in lung cancer cell lines and found that specific knockdown of S100A4 effectively suppressed cell proliferation only in lung cancer cells with S100A4-overexpression; forced expression of S100A4 accelerated cell motility only in S100A4 low-expressing lung cancer cells. PRDM2 and VASH1, identified as novel upregulated genes by microarray after specific knockdown of S100A4 in pancreatic cancer, were also analyzed, and we found that PRDM2 was significantly upregulated after S100A4-knockdown in one of two analyzed S100A4-overexpressing lung cancer cells. Our present results suggest that S100A4 plays an important role in lung carcinogenesis by means of cell proliferation and motility by a pathway similar to that in pancreatic cancer.

García-Baquero R, Puerta P, Beltran M, et al.
Methylation of tumor suppressor genes in a novel panel predicts clinical outcome in paraffin-embedded bladder tumors.
Tumour Biol. 2014; 35(6):5777-86 [PubMed] Related Publications
DNA methylation of tumor suppressor genes (TSGs) represents a frequent and early epigenetic event with potential applications for cancer detection and disease evolution. Our aim was to examine the stratification and prognostic biomarker role of the methylation of a novel panel of TSGs in bladder cancer. The methylation status of 18 TSGs was evaluated in bladder cancer cells (n=14) and paraffin-embedded primary bladder tumors (n=61), using a methylation-specific multiplex ligation-dependent probe amplification assay (MS-MLPA). Recurrence, progression, and disease-specific survival were analyzed using univariate and multivariate Cox models. PRDM2, HLTF, ID4, DLC1, BNIP3, H2AFX, CACNA1G, TGIF, and CACNA1A were discovered methylated in bladder cancer. The methylation of RUNX3 (p=0.026), TWIST1 (p=0.009), SFRP4 (p=0.002), and CCND2 (p=0.027) correlated to tumor stage. Univariate analyses indicated prognostic associations for recurrence (DLC1, SFRP5, H2AFX, CACNA1G), progression (DLC1, SFRP5, CACNA1G), disease-specific (PRDM2, DLC1, SFRP5, CACNA1G, and TIMP3), and overall survival (SFRP5 and TIMP3). In multivariate analyses, several TSGs remained as independent prognosticators for recurrence (SFRP5, H2AFX), progression (CACNA1G), and disease-specific survival (SFRP5). Thus, a novel set of TSGs was identified, frequently methylated in bladder cancer cells and tumors. TSG methylation allowed histopathologic and outcome stratification using paraffin-embedded tumors. This is clinically relevant by offering a strategy for the management of patients affected with uroepithelial neoplasias in pathology routine laboratories.

Sandahl JD, Coenen EA, Forestier E, et al.
t(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: an international study of 62 patients.
Haematologica. 2014; 99(5):865-72 [PubMed] Free Access to Full Article Related Publications
Acute myeloid leukemia with t(6;9)(p22;q34) is listed as a distinct entity in the 2008 World Health Organization classification, but little is known about the clinical implications of t(6;9)-positive myeloid leukemia in children. This international multicenter study presents the clinical and genetic characteristics of 62 pediatric patients with t(6;9)/DEK-NUP214-rearranged myeloid leukemia; 54 diagnosed as having acute myeloid leukemia, representing <1% of all childhood acute myeloid leukemia, and eight as having myelodysplastic syndrome. The t(6;9)/DEK-NUP214 was associated with relatively late onset (median age 10.4 years), male predominance (sex ratio 1.7), French-American-British M2 classification (54%), myelodysplasia (100%), and FLT3-ITD (42%). Outcome was substantially better than previously reported with a 5-year event-free survival of 32%, 5-year overall survival of 53%, and a 5-year cumulative incidence of relapse of 57%. Hematopoietic stem cell transplantation in first complete remission improved the 5-year event-free survival compared with chemotherapy alone (68% versus 18%; P<0.01) but not the overall survival (68% versus 54%; P=0.48). The presence of FLT3-ITD had a non-significant negative effect on 5-year overall survival compared with non-mutated cases (22% versus 62%; P=0.13). Gene expression profiling showed a unique signature characterized by significantly higher expression of EYA3, SESN1, PRDM2/RIZ, and HIST2H4 genes. In conclusion, t(6;9)/DEK-NUP214 represents a unique subtype of acute myeloid leukemia with a high risk of relapse, high frequency of FLT3-ITD, and a specific gene expression signature.

Hunter ZR, Xu L, Yang G, et al.
The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis.
Blood. 2014; 123(11):1637-46 [PubMed] Related Publications
The genetic basis for Waldenström macroglobulinemia (WM) remains to be clarified. Although 6q losses are commonly present, recurring gene losses in this region remain to be defined. We therefore performed whole genome sequencing (WGS) in 30 WM patients, which included germline/tumor sequencing for 10 patients. Validated somatic mutations occurring in >10% of patients included MYD88, CXCR4, and ARID1A that were present in 90%, 27%, and 17% of patients, respectively, and included the activating mutation L265P in MYD88 and warts, hypogammaglobulinemia, infection, and myelokathexis-syndrome-like mutations in CXCR4 that previously have only been described in the germline. WGS also delineated copy number alterations (CNAs) and structural variants in the 10 paired patients. The CXCR4 and CNA findings were validated in independent expansion cohorts of 147 and 30 WM patients, respectively. Validated gene losses due to CNAs involved PRDM2 (93%), BTG1 (87%), HIVEP2 (77%), MKLN1 (77%), PLEKHG1 (70%), LYN (60%), ARID1B (50%), and FOXP1 (37%). Losses in PLEKHG1, HIVEP2, ARID1B, and BCLAF1 constituted the most common deletions within chromosome 6. Although no recurrent translocations were observed, in 2 patients deletions in 6q corresponded with translocation events. These studies evidence highly recurring somatic events, and provide a genomic basis for understanding the pathogenesis of WM.

Dong SW, Li D, Xu C, et al.
Alteration in gene expression profile and oncogenicity of esophageal squamous cell carcinoma by RIZ1 upregulation.
World J Gastroenterol. 2013; 19(37):6170-7 [PubMed] Free Access to Full Article Related Publications
AIM: To investigate the effect of retinoblastoma protein-interacting zinc finger gene 1 (RIZ1) upregulation in gene expression profile and oncogenicity of human esophageal squamous cell carcinoma (ESCC) cell line TE13.
METHODS: TE13 cells were transfected with pcDNA3.1(+)/RIZ1 and pcDNA3.1(+). Changes in gene expression profile were screened and the microarray results were confirmed by reverse transcription-polymerase chain reaction (RT-PCR). Nude mice were inoculated with TE13 cells to establish ESCC xenografts. After two weeks, the inoculated mice were randomly divided into three groups. Tumors were injected with normal saline, transfection reagent pcDNA3.1(+) and transfection reagent pcDNA3.1(+)/RIZ1, respectively. Tumor development was quantified, and changes in gene expression of RIZ1 transfected tumors were detected by RT-PCR and Western blotting.
RESULTS: DNA microarray data showed that RIZ1 transfection induced widespread changes in gene expression profile of cell line TE13, with 960 genes upregulated and 1163 downregulated. Treatment of tumor xenografts with RIZ1 recombinant plasmid significantly inhibited tumor growth, decreased tumor size, and increased expression of RIZ1 mRNA compared to control groups. The changes in gene expression profile were also observed in vivo after RIZ1 transfection. Most of the differentially expressed genes were associated with cell development, supervision of viral replication, lymphocyte costimulatory and immune system development in esophageal cells. RIZ1 gene may be involved in multiple cancer pathways, such as cytokine receptor interaction and transforming growth factor beta signaling.
CONCLUSION: The development and progression of esophageal cancer are related to the inactivation of RIZ1. Virus infection may also be an important factor.

Palma P, Cuadros M, Conde-Muíño R, et al.
Microarray profiling of mononuclear peripheral blood cells identifies novel candidate genes related to chemoradiation response in rectal cancer.
PLoS One. 2013; 8(9):e74034 [PubMed] Free Access to Full Article Related Publications
Preoperative chemoradiation significantly improves oncological outcome in locally advanced rectal cancer. However there is no effective method of predicting tumor response to chemoradiation in these patients. Peripheral blood mononuclear cells have emerged recently as pathology markers of cancer and other diseases, making possible their use as therapy predictors. Furthermore, the importance of the immune response in radiosensivity of solid organs led us to hypothesized that microarray gene expression profiling of peripheral blood mononuclear cells could identify patients with response to chemoradiation in rectal cancer. Thirty five 35 patients with locally advanced rectal cancer were recruited initially to perform the study. Peripheral blood samples were obtained before neaodjuvant treatment. RNA was extracted and purified to obtain cDNA and cRNA for hybridization of microarrays included in Human WG CodeLink bioarrays. Quantitative real time PCR was used to validate microarray experiment data. Results were correlated with pathological response, according to Mandard´s criteria and final UICC Stage (patients with tumor regression grade 1-2 and downstaging being defined as responders and patients with grade 3-5 and no downstaging as non-responders). Twenty seven out of 35 patients were finally included in the study. We performed a multiple t-test using Significance Analysis of Microarrays, to find those genes differing significantly in expression, between responders (n = 11) and non-responders (n = 16) to CRT. The differently expressed genes were: BC 035656.1, CIR, PRDM2, CAPG, FALZ, HLA-DPB2, NUPL2, and ZFP36. The measurement of FALZ (p = 0.029) gene expression level determined by qRT-PCR, showed statistically significant differences between the two groups. Gene expression profiling reveals novel genes in peripheral blood samples of mononuclear cells that could predict responders and non-responders to chemoradiation in patients with locally advanced rectal cancer. Moreover, our investigation added further evidence to the importance of mononuclear cells' mediated response in the neoadjuvant treatment of rectal cancer.

Zhang Y, Owens K, Hatem L, et al.
Essential role of PR-domain protein MDS1-EVI1 in MLL-AF9 leukemia.
Blood. 2013; 122(16):2888-92 [PubMed] Free Access to Full Article Related Publications
A subgroup of leukemogenic mixed-lineage leukemia (MLL) fusion proteins (MFPs) including MLL-AF9 activates the Mecom locus and exhibits extremely poor clinical prognosis. Mecom encodes EVI1 and MDS1-EVI1 (ME) proteins via alternative transcription start sites; these differ by the presence of a PRDI-BF1-RIZ1 (PR) domain with histone methyltransferase activity in the ME isoform. Using an ME-deficient mouse, we show that ME is required for MLL-AF9-induced transformation both in vitro and in vivo. And, although Nup98-HOXA9, MEIS1-HOXA9, and E2A-Hlf could transform ME-deficient cells, both MLL-AF9 and MLL-ENL were ineffective, indicating that the ME requirement is specific to MLL fusion leukemia. Further, we show that the PR domain is essential for MFP-induced transformation. These studies clearly indicate an essential role of PR-domain protein ME in MFP leukemia, suggesting that ME may be a novel target for therapeutic intervention for this group of leukemias.

García-Baquero R, Puerta P, Beltran M, et al.
Methylation of a novel panel of tumor suppressor genes in urine moves forward noninvasive diagnosis and prognosis of bladder cancer: a 2-center prospective study.
J Urol. 2013; 190(2):723-30 [PubMed] Related Publications
PURPOSE: Changes in DNA methylation of tumor suppressor genes early in carcinogenesis represent potential indicators of cancer detection and disease evolution. We examined the diagnostic, stratification and prognostic biomarker roles in urine of the methylation of a novel panel of tumor suppressor genes in bladder cancer.
MATERIAL AND METHODS: We evaluated the methylation of 18 tumor suppressor genes in 2 prospective, independent sets of urine samples (training set of 120 preparations and validation set of 128) from patients with bladder cancer (170) and controls (78) using methylation specific multiplex ligation-dependent probe amplification. Diagnostic performance was evaluated with ROC curves. Recurrence, progression and disease specific survival were analyzed using univariate and multivariate Cox models.
RESULTS: PRDM2, HLTF, ID4, DLC1, BNIP3, H2AFX, CACNA1G, TGIF and CACNA1A were methylated in bladder cancer. CCND2, SCGB3A1, BNIP3, ID4 and RUNX3 were the most frequently methylated tumor suppressor genes in each urine set. Methylation of several tumor suppressor genes correlated with clinicopathological variables, such as stage, tumor grade, focality or age. ROC analysis revealed significant diagnostic accuracy for RUNX3 and CACNA1A in the training set, and for RUNX3 and ID4 in the validation set. On univariate and multivariate analysis CACNA1A methylation correlated with recurrence in the training set, while in the validation set PRDM2 and BNIP3 were significantly associated with recurrence and disease specific survival, respectively.
CONCLUSIONS: Tumor suppressor gene methylation allowed for histopathological and clinical stratification. Urine methylation has noninvasive usefulness not only for diagnostic assessment but also as independent bladder cancer prognosticators.

Hawley TS, Riz I, Yang W, et al.
Identification of an ABCB1 (P-glycoprotein)-positive carfilzomib-resistant myeloma subpopulation by the pluripotent stem cell fluorescent dye CDy1.
Am J Hematol. 2013; 88(4):265-72 [PubMed] Free Access to Full Article Related Publications
Multiple myeloma (MM) is characterized by the malignant expansion of differentiated plasma cells. Although many chemotherapeutic agents display cytotoxic activity toward MM cells, patients inevitably succumb to their disease because the tumor cells become resistant to the anticancer drugs. The cancer stem cell hypothesis postulates that a small subpopulation of chemotherapy-resistant cancer cells is responsible for propagation of the tumor. Herein we report that efflux of the pluripotent stem cell dye CDy1 identifies a subpopulation in MM cell lines characterized by increased expression of P-glycoprotein, a member of the ABC (ATP-binding cassette) superfamily of transporters encoded by ABCB1. We also demonstrate that ABCB1-overexpressing MM cells are resistant to the second-generation proteasome inhibitor carfilzomib that recently received accelerated approval for the treatment of therapy-refractive MM by the U.S. Food and Drug Administration. Moreover, increased resistance to carfilzomib in sensitive MM cells following drug selection was associated with upregulation of ABCB1 cell-surface expression which correlated with increased transporter activity as measured by CDy1 efflux. We further show that chemosensitization of MM cells to carfilzomib could be achieved in vitro by cotreatment with vismodegib, a hedgehog pathway antagonist which is currently in MM clinical trials. CDy1 efflux may therefore be a useful assay to determine whether high expression of ABCB1 is predictive of poor clinical responses in MM patients treated with carfilzomib. Our data also suggest that inclusion of vismodegib might be a potential strategy to reverse ABCB1-mediated drug resistance should it occur.

Khaenam P, Niibori A, Okada S, et al.
Contribution of RIZ1 to regulation of proliferation and migration of a liver fluke-related cholangiocarcinoma cell.
Asian Pac J Cancer Prev. 2012; 13(8):4007-11 [PubMed] Related Publications
PURPOSE: Retinoblastoma-interacting zinc finger gene (RIZ1) is a tumor suppressor gene which is highly inactivated by promoter hypermethylation in patients with liver fluke-related cholangiocarcinoma (CCA). Epigenetic aberration of this gene might withdraw the ability to restrain tumor cell proliferation and migration. We aimed to define the role of RIZ1 on cell proliferation and migration in CCA cell line.
MATERIALS AND METHODS: Small interference RNA (siRNA) was used to knock down the expression of RIZ1 in a CCA-derived cell line in which cell proliferation and cell migration were performed.
RESULTS: A predominant nuclear localization of RIZ1 was observed. Reduction of RIZ1 by siRNA augmented cell proliferation and migration.
CONCLUSION: The result suggested that RIZ1 might play a role in regulating cell proliferation and migration in CCA. Reduction of RIZ1 expression may aggravate the progression of CCA.

Liu ZY, Wang JY, Liu HH, et al.
Retinoblastoma protein-interacting zinc-finger gene 1 (RIZ1) dysregulation in human malignant meningiomas.
Oncogene. 2013; 32(10):1216-22 [PubMed] Related Publications
Retinoblastoma protein-interacting zinc-finger gene 1 (RIZ1) expression is often silenced in many types of human tumors. However, the relationship between RIZ1 expression and malignant meningiomas remains unclear. Here we have found for the first time that the expression of RIZ1 genes are associated with meningiomas progression through extensive analyses of Affymetrix GeneChip microarray data. Further validation methods for gene expression included quantitative PCR (qPCR), western blot and immunohistochemistry analysis, and these methods confirmed that RIZ1 is significantly downregulated in malignant meningioma tissues, as compared with benign meningiomas. In addition, malignant meningioma cells were stably transfected with ectogenic RIZ1 using Lentivirus-mediated transfection, and the transfections were followed by an in vitro 5-bromo-2-deoxyuridin incorporation assay, colony formation assay, cell cycle analysis, invasive analysis, apoptotic assay and western blot analysis. Our results demonstrate that the forced expression of RIZ1 in a malignant meningioma cell line inhibited cellular proliferation and arrested the cells in the G2/M phase of the cell cycle. We also confirmed that overexpression of RIZ1 may induce apoptosis of malignant meningioma cells. Furthermore, RIZ1 overexpression in malignant meningioma cells was associated with the downregulation of c-myc expression. These results from our study indicate that RIZ1 expression is significantly downregulated as the formation of meningiomas progressed, and suggest that RIZ1 may represent a promising candidate tumor suppressor gene that contributes to malignant meningiomas.

Persson M, Andrén Y, Moskaluk CA, et al.
Clinically significant copy number alterations and complex rearrangements of MYB and NFIB in head and neck adenoid cystic carcinoma.
Genes Chromosomes Cancer. 2012; 51(8):805-17 [PubMed] Related Publications
Adenoid cystic carcinoma (ACC) of the head and neck is a malignant tumor with poor long-term prognosis. Besides the recently identified MYB-NFIB fusion oncogene generated by a t(6;9) translocation, little is known about other genetic alterations in ACC. Using high-resolution, array-based comparative genomic hybridization, and massively paired-end sequencing, we explored genomic alterations in 40 frozen ACCs. Eighty-six percent of the tumors expressed MYB-NFIB fusion transcripts and 97% overexpressed MYB mRNA, indicating that MYB activation is a hallmark of ACC. Thirty-five recurrent copy number alterations (CNAs) were detected, including losses involving 12q, 6q, 9p, 11q, 14q, 1p, and 5q and gains involving 1q, 9p, and 22q. Grade III tumors had on average a significantly higher number of CNAs/tumor compared to Grade I and II tumors (P = 0.007). Losses of 1p, 6q, and 15q were associated with high-grade tumors, whereas losses of 14q were exclusively seen in Grade I tumors. The t(6;9) rearrangements were associated with a complex pattern of breakpoints, deletions, insertions, inversions, and for 9p also gains. Analyses of fusion-negative ACCs using high-resolution arrays and massively paired-end sequencing revealed that MYB may also be deregulated by other mechanisms in addition to gene fusion. Our studies also identified several down-regulated candidate tumor suppressor genes (CTNNBIP1, CASP9, PRDM2, and SFN) in 1p36.33-p35.3 that may be of clinical significance in high-grade tumors. Further, studies of these and other potential target genes may lead to the identification of novel driver genes in ACC.

Nishida N, Kudo M, Nagasaka T, et al.
Characteristic patterns of altered DNA methylation predict emergence of human hepatocellular carcinoma.
Hepatology. 2012; 56(3):994-1003 [PubMed] Related Publications
UNLABELLED: We aimed to identify the specific subset of tumor suppressor genes (TSGs) that are methylation-silenced during the earliest steps of hepatocarcinogenesis, and to further evaluate whether these genes can serve as predictive biomarkers of hepatocellular carcinoma (HCC) emergence. A total of 482 liver tissues including 177 pairs of HCCs and matched nontumor livers and 128 liver biopsies from chronic hepatitis C (CHC) patients were analyzed for quantitative methylation analysis in 24 TSG promoters and three MINT loci. The tumors were classified as early, less-progressed, and highly progressed HCCs using histology and radiological approaches. A subset of TSGs that harbored distinctly high levels of methylation in early HCCs were selected. Based on the methylation profiles of these genes, Kaplan-Meier analyses were performed to determine time-to-HCC occurrence in CHC patients. Subsequently, multivariate analysis was performed using age, gender, fibrosis stage, and number of methylated TSGs as covariates. Among TSGs analyzed, a subset of eight TSGs (HIC1, GSTP1, SOCS1, RASSF1, CDKN2A, APC, RUNX3, and PRDM2) demonstrated a distinct cluster by hierarchical clustering and receiver operating characteristic analyses. This subset of TSGs showed significantly higher methylation levels in the early HCCs (P < 0.0001). In the CHC patients, methylation frequencies in these TSGs were associated with shorter time-to-HCC occurrence (P < 0.0001), and number of methylated genes was an independent risk factor for HCC (hazard ratio = 5.21, 95% confidence interval = 2.25-11.76, P = 0.0002).
CONCLUSION: Epigenetic inactivation of a subset of TSGs plays a critical role in the earliest steps of hepatocarcinogenesis. Furthermore, epigenetic inactivation of these genes in CHC provides a prognostic value for determining the risk for developing HCC later in life.

Dong SW, Cui YT, Zhong RR, et al.
Decreased expression of retinoblastoma protein-interacting zinc-finger gene 1 in human esophageal squamous cell cancer by DNA methylation.
Clin Lab. 2012; 58(1-2):41-51 [PubMed] Related Publications
BACKGROUND: To study the expression of the RIZ1 (Retinoblastoma protein-interacting zinc-finger gene 1) gene and investigate the promoter region methylation status of RIZ1 gene in the human esophageal squamous cell carcinoma (ESCC) cell lines of KYSE150, KYSE510, TE13, EC9706, CaEsl7, and EC109. To investigate the influence of DNMT (DNA methyltransferase) 5-aza-CdR(5-aza-2'-deoxycytidine) on the transcription of the RIZ1 gene in one cell line whose RIZ1 gene promoter region methylation was detected, and to investigate its influence on the cell proliferation.
METHODS: Real-time PCR (Real-time quantitative PCR) and an immunohistochemistry technique was used to get the expression of RIZ1 in specimens from 6 human ESCC cell lines and 28 ESCC patients (tumor tissues and adjacent non-cancerous tissues). MSP (Methylation-specific PCR) was used to investigate the promoter region methylation status of the RIZ1 gene in the 6 ESCC cell lines. One cell line, whose RIZ1 gene promoter region methylation was detected, was chosen for the next studies in which it was treated it by with 5-aza-CdR. Real-time PCR was used to investigate its influence on the transcription of RIZ1 gene and MTT (methyl thiazolyl tetrazolium) was used to detect if 5-aza-CdR inhibits the proliferation of the cell line.
RESULTS: In the 28 ESCC patient samples, RIZ1 expression was significantly lower in the tumor tissues than that in their adjacent non-cancerous tissues (p < 0.05). Consistently, immunohistochemistry analyses of RIZ1 protein expression showed that in the ESCC tissues RIZ1 protein expression was also significantly lower than in the adjacent tissues. In the human ESCC tissues the rate of expression accounts for 0% (0/12), and in the adjacent noncancerous tissues the rate of expression was 66.7% (8/12), the correlation was highly significant (chi2 = 12.000, p < 0.05). Promoter methylation of the RIZ1 gene was detected in TE13, CaEsl7, EC109. The cell line TE13 was chosen for the next studies. The expression of RIZ1 mRNA in TE-13 was up-regulated after having been treated with 5-aza-CdR. 5-aza-CdR inhibited cell proliferation of TE-13 in a time and concentration-dependent manner.
CONCLUSIONS: Promoter methylation may play an important role in the epigenetic silencing of RIZ1 gene expression. Methylation of the RIZ1 promoter and loss of RIZ1 expression in human ESCC are independent biomarkers. Their determination may offer guidance for selecting appropriate diagnoses and treatments. RIZ1 may be a potential tumor suppressor in human ESCC.

Dong SW, Zhang P, Liu YM, et al.
Study on RIZ1 gene promoter methylation status in human esophageal squamous cell carcinoma.
World J Gastroenterol. 2012; 18(6):576-82 [PubMed] Free Access to Full Article Related Publications
AIM: To investigate the promoter region methylation status of retinoblastoma protein-interacting zinc finger gene 1 (RIZ1) in the human esophageal squamous cell carcinoma (ESCC) cell lines and tissues and verify the relationship between methylation of RIZ1 and oncogenesis, tumor progression and metastasis etc of ESCC.
METHODS: Methylation-specific polymerase chain reaction (MSP) was used to investigate the promoter region methylation status of RIZ1 in 6 ESCC cell lines. One cell line where RIZ1 promoter region methylation was detected was selected for the next study, where the cell line was treated with 5-aza-CdR. Real-time polymerase chain reaction was used to investigate its influence on the transcription of RIZ1. Experiments using frozen pathological specimens from 47 ESCC patients were performed using the same MSP methodology.
RESULTS: Promoter methylation of RIZ1 gene was detected in TE13, CaEs17 and EC109 cell lines and the cell line TE13 was chosen for further study. The expression of RIZ1 mRNA in TE-13 was up-regulated after treatment with 5-aza-CdR. The rate of methylation in carcinomas tissues was significantly higher than those in matched neighboring normal and distal ending normal tissue, and the deviation of data was statistically significant (χ(2) = 24.136, P < 0.01). Analysis of the gender, age familial history, tumour deviation, tumour saturation, lymph gland displacement and clinical staging of 47 samples from ESCC patients showed that the fluctuation of data was not statistically significant.
CONCLUSION: Promoter methylation may play an important role in the epigenetic silencing of RIZ1 gene expression in human ESCC. RIZ1 is considered to be a potential tumor suppressor gene and may be a biological parameter for testing early stage human ESCC.

Shimura H, Mori N, Wang YH, et al.
Aberrant methylation and decreased expression of the RIZ1 gene are frequent in adult acute lymphoblastic leukemia of T-cell phenotype.
Leuk Lymphoma. 2012; 53(8):1599-609 [PubMed] Related Publications
Retinoblastoma protein-interacting zinc finger, RIZ1, is a tumor suppressor gene that is inactivated in various solid tumors. However, the role of the RIZ1 gene has not been well examined in adult acute lymphoblastic leukemia (ALL). We analyzed the expression and promoter methylation status of the RIZ1 gene in patients with newly diagnosed ALL by quantitative real-time reverse transcription polymerase chain reaction (PCR) and methylation-specific PCR, respectively. RIZ1 expression in 67 cases of ALL (mean 1.043) was decreased compared with that in normal bone marrow (mean 1.471) (p = 0.030). Methylation was detected in 11 of 71 patients (15.5%) but not in healthy controls. Methylation was associated with decreased RIZ1 expression in many ALL cases examined, but this was not statistically significant. In T-ALL, RIZ1 methylation was more frequent (63.6%) than in B-ALL (6.7%) (p < 0.0001) and the decrease of RIZ1 expression was more significant than in B-ALL (p = 0.045). 5-Aza-2'-deoxycytidine treatment of MOLT-4 cells with RIZ1 methylation induced demethylation of RIZ1 and restoration of expression. Forced RIZ1 expression in T-ALL cell lines suppressed cell growth accompanied by G2/M arrest and apoptosis. No mutations were found by PCR-single strand conformation polymorphism analysis in hotspots of the gene. These results suggest that RIZ1 is inactivated in adult ALL, and this inactivation is associated with methylation in T-ALL.

Shu XS, Geng H, Li L, et al.
The epigenetic modifier PRDM5 functions as a tumor suppressor through modulating WNT/β-catenin signaling and is frequently silenced in multiple tumors.
PLoS One. 2011; 6(11):e27346 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: PRDM (PRDI-BF1 and RIZ domain containing) proteins are zinc finger proteins involved in multiple cellular regulations by acting as epigenetic modifiers. We studied a recently identified PRDM member PRDM5 for its epigenetic abnormality and tumor suppressive functions in multiple tumorigeneses.
METHODOLOGY/PRINCIPAL FINDINGS: Semi-quantitative RT-PCR showed that PRDM5 was broadly expressed in human normal tissues, but frequently silenced or downregulated in multiple carcinoma cell lines due to promoter CpG methylation, including 80% (4/5) nasopharyngeal, 44% (8/18) esophageal, 76% (13/17) gastric, 50% (2/4) cervical, and 25% (3/12) hepatocellular carcinoma cell lines, but not in any immortalized normal epithelial cell lines. PRDM5 expression could be restored by 5-aza-2'-deoxycytidine demethylation treatment in silenced cell lines. PRDM5 methylation was frequently detected by methylation-specific PCR (MSP) in multiple primary tumors, including 93% (43/46) nasopharyngeal, 58% (25/43) esophageal, 88% (37/42) gastric and 63% (29/46) hepatocellular tumors. PRDM5 was further found a stress-responsive gene, but its response was impaired when the promoter was methylated. Ectopic PRDM5 expression significantly inhibited tumor cell clonogenicity, accompanied by the inhibition of TCF/β-catenin-dependent transcription and downregulation of CDK4, TWIST1 and MDM2 oncogenes, while knocking down of PRDM5 expression lead to increased cell proliferation. ChIP assay showed that PRDM5 bound to its target gene promoters and suppressed their transcription. An inverse correlation between the expression of PRDM5 and activated β-catenin was also observed in cell lines.
CONCLUSIONS/SIGNIFICANCE: PRDM5 functions as a tumor suppressor at least partially through antagonizing aberrant WNT/β-catenin signaling and oncogene expression. Frequent epigenetic silencing of PRDM5 is involved in multiple tumorigeneses, which could serve as a tumor biomarker.

Riz I, Zweier-Renn LA, Toma I, et al.
Apoptotic role of IKK in T-ALL therapeutic response.
Mol Cancer Res. 2011; 9(8):979-84 [PubMed] Free Access to Full Article Related Publications
Despite considerable progress in the treatment of T cell acute lymphoblastic leukemia (T-ALL), it is still the highest risk malignancy among ALL. The outcome of relapsed patients remains dismal. The pro-survival role of NOTCH1 and NFκB in T-ALL is well documented; also, both factors were reported to be predictive of relapse. The NOTCH1 signaling pathway, commonly activated in T-ALL, was shown to enhance the transcriptional function of NFκB via several mechanisms. Thus, pharmacological inhibition of NOTCH1-NFκB signaling was suggested to be incorporated into existing T-ALL treatment protocols. However, conventional chemotherapy is based on activation of various types of stress, such as DNA damage, mitotic perturbations or endoplasmic reticulum overload. NFκB is frequently activated in response to stress and, depending on yet unknown mechanisms, it either protects cells from the drug action or mediates apoptosis. Here, we report that T-ALL cells respond to NFκB inhibition in opposite ways depending on whether they were treated with a stress-inducing chemotherapeutic agent or not. Moreover, we found that NOTCH1 enhances NFκB apoptotic function in the stressed cells. The data argue for further studies of NFκB status in T-ALL patients on different treatment protocols and the impact of activating NOTCH1 mutations on treatment response.

Hutajulu SH, Indrasari SR, Indrawati LP, et al.
Epigenetic markers for early detection of nasopharyngeal carcinoma in a high risk population.
Mol Cancer. 2011; 10:48 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Undifferentiated nasopharyngeal carcinoma (NPC) is strongly related to Epstein-Barr virus (EBV) infection, allowing aberrant antibodies against EBV and viral DNA load as screening tools in high risk populations. Methylation analysis in the promoter of tumor suppressor genes (TSGs) may serve as a complementary marker for identifying early cases. This study determined methylation status of multiple TSGs and evaluated whether it may improve early detection.
METHODS: Nasopharyngeal brushings were taken from 53 NPC patients, 22 high risk subjects and 25 healthy EBV carriers. Corresponding NPC paraffin tissue was included. DNA was bisulfite-modified preceding analysis by methylation-specific PCR (MSP). Ten TSGs were studied.
RESULTS: NPC paraffin and brushing DNA revealed an 81.8% concordance so that MSP analysis was done using either one of both specimens. NPC samples showed methylation for individual TSGs (DAPK1 79.2%, CDH13 77.4%, DLC1 76.9%, RASSF1A 75.5%, CADM1 69.8%, p16 66.0%, WIF1 61.2%, CHFR 58.5%, RIZ1 56.6% and RASSF2A 29.2%). High risk individuals, having elevated EBV IgA and viral load, showed high frequency of methylation of CDH13, DAPK1, DLC1 and CADM1, but low frequency of methylation of p16 and WIF1 and undetectable methylation of RASSF1A, CHFR, RIZ1 and RASSF2A. Healthy subjects showed similar patterns as high risk individuals. A combination of RASSF1A and p16 gave good discrimination between NPC and non-NPC, but best results were combined analysis of five methylation markers (RASSF1A, p16, WIF1, CHFR and RIZ1) with detection rate of 98%.
CONCLUSION: Multiple marker MSP is proposed as a complementary test for NPC risk assessment in combination with EBV-based markers.

Abbondanza C, De Rosa C, D'Arcangelo A, et al.
Identification of a functional estrogen-responsive enhancer element in the promoter 2 of PRDM2 gene in breast cancer cell lines.
J Cell Physiol. 2012; 227(3):964-75 [PubMed] Related Publications
The retinoblastoma protein-interacting zinc-finger (RIZ) gene, also known as PRDM2, encodes two protein products, RIZ1 and RIZ2, differing for the presence of a 202 aa domain, called PR domain, at the N-terminus of the RIZ1 molecule. While the histone H3 K9 methyltransferase activity of RIZ1 is associated with the negative control of cell proliferation, no information is currently available on either expression regulation of the RIZ2 form or on its biological activity. RIZ proteins act as ER co-activators and promote optimal estrogen response in female reproductive tissues. In estrogen-responsive cells, 17-β estradiol modulates RIZ gene expression producing a shift in the balanced expression of the two forms. Here, we demonstrate that an estrogen-responsive element (ERE) within the RIZ promoter 2 is regulated in a ligand-specific manner by ERα, through both the AF1 and AF2 domains. The pattern of ERα binding, histone H4 acetylation, and histone H3 cyclical methylation of lysine 9 was comparable to other estrogen-regulated promoters. Association of topoisomerase IIβ with the RIZ promoter 2 confirmed the transcriptional activation induced by estrogen. We hypothesize that RIZ2, acting as a negative regulator of RIZ1 function, mediates the proliferative effect of estrogen through regulation of survival and differentiation gene expression.

Sun W, Qiao L, Liu Q, et al.
Anticancer activity of the PR domain of tumor suppressor RIZ1.
Int J Med Sci. 2011; 8(2):161-7 [PubMed] Free Access to Full Article Related Publications
Human tumor suppressor gene RIZ encodes two protein products, tumor suppressor RIZ1 and proto-oncoprotein RIZ2, which regulate cellular functions in a Yin-Yang fashion. The only structural difference between them is that RIZ2 lacks the N-terminal PR domain. In this study, we showed that RIZ1 mRNA expression level was elevated in stage IV of eight different types of cancer (stage III for prostate cancer), indicating that RIZ1 might play an important role in tumor metastasis, and the PR domain alone possessed anticancer activity.

Ren TN, Wang JS, He YM, et al.
Effects of SMYD3 over-expression on cell cycle acceleration and cell proliferation in MDA-MB-231 human breast cancer cells.
Med Oncol. 2011; 28 Suppl 1:S91-8 [PubMed] Related Publications
SET and MYND domain-containing protein 3 (SMYD3) is a histone methyltransferase that plays an important role in transcriptional regulation in human carcinogenesis. It can specifically methylate histone H3 at lysine 4 and activate the transcription of a set of downstream genes, including several oncogenes (e.g., N-myc, CrkL, Wnt10b, RIZ and hTERT) and genes involved in the control of cell cycle (e.g., CyclinG1 and CDK2) and signal transduction (e.g., STAT1, MAP3K11 and PIK3CB). To determine the effects of SMYD3 over-expression on cell proliferation, we transfected SMYD3 into MDA-MB-231 cells and found that these cells showed several transformed phenotypes as demonstrated by colony growth in soft agar. Besides, we show here that down-regulation of SMYD3 could induce G1-phase cell cycle arrest, indicating the potent induction of apoptosis by SMYD3 knockdown. These results suggest the regulatory mechanisms of SMYD3 on the acceleration of cell cycle and facilitate the development of strategies that may inhibit the progression of cell cycle in breast cancer cells.

Geli J, Kiss N, Kogner P, Larsson C
Suppression of RIZ in biologically unfavourable neuroblastomas.
Int J Oncol. 2010; 37(5):1323-30 [PubMed] Related Publications
Neuroblastoma is a paediatric solid tumor characterized by recurrent genomic abnormalities of prognostic importance. One of the most commonly observed abnormalities is deletion of the short arm of chromosome 1 and reduced expression of cancer related genes in this chromosomal arm. The long isoform of the retinoblastoma protein-interacting zink finger gene (RIZ1) is a known tumor suppressor and a candidate neuroblastoma gene located at 1p36.2. The present study was undertaken to further assess the possible involvement of RIZ in neuroblastoma development. Expression of RIZ transcripts were quantified in a panel of neuroblastoma cell lines and tumors (33 neuroblastomas and 3 ganglioneuromas). Methylation status of promoter P1 driving RIZ1 expression was quantified by bisulfite Pyrosequencing. Only low mean levels of promoter methylation (<10%) were observed in all samples. However, RIZ1 and RIZ1+2 mRNA were significantly under-expressed in biologically unfavourable tumors characterized by 1p loss (p<0.005) or MYCN amplification (p<0.005). Suppression of RIZ1 is likely to contribute to the pathogenesis of biologically unfavourable neuroblastomas. In contrast to multiple other neoplasias, RIZ1 promoter methylation is not a common event in neuroblastoma.

Mori N, Yoshinaga K, Tomita K, et al.
Aberrant methylation of the RIZ1 gene in myelodysplastic syndrome and acute myeloid leukemia.
Leuk Res. 2011; 35(4):516-21 [PubMed] Related Publications
We performed methylation specific PCR analysis on the RIZ1 promoter in MDS and AML. Methylation was detected in 17 of 34 MDS (50%) and 22 of 72 AML (31%) (p=0.053). Methylation was detected in eleven of 17 secondary AML from MDS (65%), and eleven of 55 de novo AML (20%) (p=0.0005). Bisulfite sequence revealed methylation at many CpG sites in the promoter. Decreased RIZ1 expression was accompanied by methylation in six of nine samples examined, while it was also observed in seven of 13 without methylation. Treatment of AML cells, that have RIZ1 methylation, with 5-Aza-dC, induced growth suppression with RIZ1 restoration. Our results suggest that the RIZ1 gene is inactivated in MDS and AML in part by methylation, whereas another mechanism should be involved in others.

Formeister EJ, Tsuchiya M, Fujii H, et al.
Comparative analysis of promoter methylation and gene expression endpoints between tumorous and non-tumorous tissues from HCV-positive patients with hepatocellular carcinoma.
Mutat Res. 2010; 692(1-2):26-33 [PubMed] Free Access to Full Article Related Publications
Transcriptional silencing of tumor suppressor genes and other cancer-related genes induced by promoter CpG island hypermethylation is an important epigenetic mechanism of hepatocarcinogenesis. Previous studies have established methylation profiles of hepatocellular carcinomas (HCCs) and demonstrated that methylation of several candidate genes in resected tissues may be associated with time to recurrence. The goals of our study were to test whether specific promoter methylation and mRNA levels of candidate genes, as well as global changes in DNA methylation, can be linked with time to recurrence and clinicopathological variables in a homogenous study group of HCC patients. Forty-three tumorous and 45 non-tumorous liver tissue samples from the surgical margin were obtained from HCV-positive, HBV-negative HCC patients who underwent tumor resection surgery and who were monitored for tumor recurrence thereafter (median follow-up time: 16 months (range, 0-79 months)). Methylation-specific PCR was used to assess the promoter methylation status of P16(INK4a), SOCS-1, RASSF1A, APC, GSTP1, RIZ1, and MGMT genes, while the level of LINE-1 methylation was used as marker of global DNA methylation levels. Methylation frequencies in P16(INK4a), RASSF1A, APC, GSTP1, and RIZ1 genes were significantly greater in tumorous versus non-tumorous tissues. Methylation of RIZ1 in non-tumorous tissues was significantly associated with time to recurrence. Additionally, genomic DNA was significantly more hypomethylated in tumorous tissues, and this change was associated with shorter recurrence, but not with clinicopathological features. In conclusion, this study supports the role of aberrant methylation in the pathobiology of HCV-positive HCCs. The finding that RIZ1 methylation and increased levels of LINE-1 hypomethylation in non-tumorous tissues are associated with time to recurrence underscores the importance of assessing the epigenetic state of the liver remnant.

Zhang C, Li H, Wang Y, et al.
Epigenetic inactivation of the tumor suppressor gene RIZ1 in hepatocellular carcinoma involves both DNA methylation and histone modifications.
J Hepatol. 2010; 53(5):889-95 [PubMed] Related Publications
BACKGROUND & AIMS: The retinoblastoma-interacting zinc finger gene RIZ1 is inactivated in many cancers, but the underlying mechanisms remain unknown. This study aimed to investigate the epigenetic mechanisms of RIZ1 inactivation by analyzing the relationship between DNA methylation and histone modifications during regulation of RIZ1 expression.
METHODS: Methylation-specific PCR, RT-PCR, and immunohistochemistry were performed to examine RIZ1 methylation and expression. Dynamic changes in histone H3 lysine 9 (H3K9) modifications and histone deacetylases (HDACs) associated with the promoter were analyzed by chromatin immunoprecipitation (ChIP).
RESULTS: RIZ1 methylation was detected in 66.7% (32/48) HCC tissues, 6.3% (3/48) corresponding non-cancerous tissues, and 66.7% (4/6) HCC cell lines. All 32 HCC tissues with promoter methylation showed complete loss of RIZ1 protein, whereas RIZ1 protein was present in all the corresponding non-cancerous tissues. Neither 5-aza-2-deoxycitidine (5-Aza-dC) nor Trichostatin A (TSA) reversed promoter methylation, but did restore RIZ1 mRNA and resulted in the downregulation of HDAC1 but not HDAC3. However, 5-Aza-dC+TSA induced a partial reversal of promoter methylation and a markedly synergistic reactivation of RIZ1. Moreover, both HDAC1 and HDAC3 were downregulated. The ChIP assays showed 5-Aza-dC and/or TSA also contributed to the dynamic conversion of trimethylated to acetylated H3K9 at the promoter. Furthermore, a decrease in H3K9 trimethylation preceded an increase in H3K9 acetylation.
CONCLUSIONS: Our results suggest that promoter methylation and H3K9 modifications work together to silence the RIZ1 gene in HCC. 5-Aza-dC can restore the expression of RIZ1, as reflected by its effects on histone modification levels. This finding indicates that cooperative effects between these epigenetic modifications exist.

Riz I, Hawley TS, Luu TV, et al.
TLX1 and NOTCH coregulate transcription in T cell acute lymphoblastic leukemia cells.
Mol Cancer. 2010; 9:181 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The homeobox gene TLX1 (for T-cell leukemia homeobox 1, previously known as HOX11) is inappropriately expressed in a major subgroup of T cell acute lymphoblastic leukemia (T-ALL) where it is strongly associated with activating NOTCH1 mutations. Despite the recognition that these genetic lesions cooperate in leukemogenesis, there have been no mechanistic studies addressing how TLX1 and NOTCH1 functionally interact to promote the leukemic phenotype.
RESULTS: Global gene expression profiling after downregulation of TLX1 and inhibition of the NOTCH pathway in ALL-SIL cells revealed that TLX1 synergistically regulated more than 60% of the NOTCH-responsive genes. Structure-function analysis demonstrated that TLX1 binding to Groucho-related TLE corepressors was necessary for maximal transcriptional regulation of the NOTCH-responsive genes tested, implicating TLX1 modulation of the NOTCH-TLE regulatory network. Comparison of the dataset to publicly available biological databases indicated that the TLX1/NOTCH-coregulated genes are frequently targeted by MYC. Gain- and loss-of-function experiments confirmed that MYC was an essential mediator of TLX1/NOTCH transcriptional output and growth promotion in ALL-SIL cells, with TLX1 contributing to the NOTCH-MYC regulatory axis by posttranscriptional enhancement of MYC protein levels. Functional classification of the TLX1/NOTCH-coregulated targets also showed enrichment for genes associated with other human cancers as well as those involved in developmental processes. In particular, we found that TLX1, NOTCH and MYC coregulate CD1B and RAG1, characteristic markers of early cortical thymocytes, and that concerted downregulation of the TLX1 and NOTCH pathways resulted in their irreversible repression.
CONCLUSIONS: We found that TLX1 and NOTCH synergistically regulate transcription in T-ALL, at least in part via the sharing of a TLE corepressor and by augmenting expression of MYC. We conclude that the TLX1/NOTCH/MYC network is a central determinant promoting the growth and survival of TLX1+ T-ALL cells. In addition, the TLX1/NOTCH/MYC transcriptional network coregulates genes involved in T cell development, such as CD1 and RAG family members, and therefore may prescribe the early cortical stage of differentiation arrest characteristic of the TLX1 subgroup of T-ALL.

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