SUV39H1

Gene Summary

Gene:SUV39H1; suppressor of variegation 3-9 homolog 1
Aliases: MG44, KMT1A, SUV39H, H3-K9-HMTase 1
Location:Xp11.23
Summary:This gene encodes an evolutionarily-conserved protein containing an N-terminal chromodomain and a C-terminal SET domain. The encoded protein is a histone methyltransferase that trimethylates lysine 9 of histone H3, which results in transcriptional gene silencing. Loss of function of this gene disrupts heterochromatin formation and may cause chromosome instability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:histone-lysine N-methyltransferase SUV39H1
Source:NCBIAccessed: 13 March, 2017

Ontology:

What does this gene/protein do?
Show (22)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 13 March 2017 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.

  • DNA-Binding Proteins
  • Chromatin Immunoprecipitation
  • Apoptosis
  • X Chromosome
  • Carcinogenesis
  • Breast Cancer
  • Transcription
  • Cell Proliferation
  • Epigenetics
  • Proto-Oncogene Proteins
  • Acute Myeloid Leukaemia
  • Tumor Suppressor Proteins
  • DNA (Cytosine-5-)-Methyltransferase
  • HEK293 Cells
  • MicroRNAs
  • DNA Methylation
  • Leukaemia
  • Mutation
  • Methyltransferases
  • Enzyme Inhibitors
  • U937 Cells
  • Lung Cancer
  • Promoter Regions
  • Methylation
  • Xenograft Models
  • Transcription Factors
  • Pancreatic Cancer
  • HeLa Cells
  • Histones
  • ras Proteins
  • Protein Methyltransferases
  • Cancer Gene Expression Regulation
  • Repressor Proteins
  • Histone-Lysine N-Methyltransferase
  • Gene Silencing
  • Histone Deacetylase Inhibitors
  • Prostate Cancer
  • p53 Protein
  • Down-Regulation
  • Messenger RNA
  • siRNA
  • Lysine
  • Up-Regulation
  • Protein Transport
Tag cloud generated 13 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: SUV39H1 (cancer-related)

Liao HF, Lee CC, Hsiao PC, et al.
TCH1036, a indeno[1,2-c]quinoline derivative, potentially inhibited the growth of human brain malignant glioma (GBM) 8401 cells via suppression of the expression of Suv39h1 and PARP.
Biomed Pharmacother. 2016; 82:649-59 [PubMed] Related Publications
A newly synthesized Indeno[1,2-c]quinoline derivative, which has previously been found to potentially trap DNA-topoisomerase cleavage complexes more effectively than camptothecin, could effectively inhibit the proliferation of a variety of cancers, such as breast cancer treated with TCH1030. In this study, we further explore the activity of the TCH1036, TCH1259 and TCH1030 compounds in suppressing the growth of human brain malignant glioma (GBM) 8401 cells, in addition to elucidating the related mechanisms. According to tests of cytotoxicity, the GBM cells were more sensitive to the inhibitory effects of the TCH1036 compound than to those of the other two compounds. Moreover, the accumulation of GBM cells in the sub-G1 and G2/M phases was clearly induced by the TCH1036 compound in a dose-dependent manner. A screening of the majority of histone-modifier enzymes indicated that the expression of Suv39h1 in the GBM cells was attenuated by treatment with each of the TCH compounds, an observation which was further confirmed by Western blotting. The increase in active-form caspase 3 in the GBM cells treated with TCH compounds caused a high degree of poly (ADP-ribose) polymerase (PARP) cleavage and also enhanced the high ratio of hypodiploid GBM cells in the sub-G1 phase. In molecular docking simulations, it was observed that the stable forms of the TCH compounds could successfully insert into the catalytic pocket of PARP, with the highest affinity being between PARP and the TCH1036 compound. These findings suggested that the TCH1036 compound would be a promising compound in the treatment of brain malignant glioma.

Rondinelli B, Rosano D, Antonini E, et al.
Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer.
J Clin Invest. 2015; 125(12):4625-37 [PubMed] Free Access to Full Article Related Publications
Mutations in genes encoding chromatin-remodeling proteins are often identified in a variety of cancers. For example, the histone demethylase JARID1C is frequently inactivated in patients with clear cell renal cell carcinoma (ccRCC); however, it is largely unknown how JARID1C dysfunction promotes cancer. Here, we determined that JARID1C binds broadly to chromatin domains characterized by the trimethylation of lysine 9 (H3K9me3), which is a histone mark enriched in heterochromatin. Moreover, we found that JARID1C localizes on heterochromatin, is required for heterochromatin replication, and forms a complex with established players of heterochromatin assembly, including SUV39H1 and HP1α, as well as with proteins not previously associated with heterochromatin assembly, such as the cullin 4 (CUL4) complex adaptor protein DDB1. Transcription on heterochromatin is tightly suppressed to safeguard the genome, and in ccRCC cells, JARID1C inactivation led to the unrestrained expression of heterochromatic noncoding RNAs (ncRNAs) that in turn triggered genomic instability. Moreover, ccRCC patients harboring JARID1C mutations exhibited aberrant ncRNA expression and increased genomic rearrangements compared with ccRCC patients with tumors endowed with other genetic lesions. Together, these data suggest that inactivation of JARID1C in renal cancer leads to heterochromatin disruption, genomic rearrangement, and aggressive ccRCCs. Moreover, our results shed light on a mechanism that underlies genomic instability in sporadic cancers.

Mo W, Liu Q, Lin CC, et al.
mTOR Inhibitors Suppress Homologous Recombination Repair and Synergize with PARP Inhibitors via Regulating SUV39H1 in BRCA-Proficient Triple-Negative Breast Cancer.
Clin Cancer Res. 2016; 22(7):1699-712 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease and has the worst outcome among all subtypes of breast cancers. Although PARP inhibitors represent a promising treatment in TNBC with BRCA1/BRCA2 mutations, there is great interest in identifying drug combinations that can extend the use of PARP inhibitors to a majority of TNBC patients with wild-type BRCA1/BRCA2 Here we explored whether mTOR inhibitors, through modulating homologous recombination (HR) repair, would provide therapeutic benefit in combination with PARP inhibitors in preclinical models of BRCA-proficient TNBC.
EXPERIMENTAL DESIGN: We have studied the effects of mTOR inhibitors on HR repair following DNA double-strand breaks (DSB). We further demonstrated the in vitro and in vivo activities of combined treatment of mTOR inhibitors with PARP inhibitors in BRCA-proficient TNBC. Moreover, microarray analysis and rescue experiments were used to investigate the molecular mechanisms of action.
RESULTS: We found that mTOR inhibitors significantly suppressed HR repair in two BRCA-proficient TNBC cell lines. mTOR inhibitors and PARP inhibitors in combination exhibited strong synergism against these TNBC cell lines. In TNBC xenografts, we observed enhanced efficacy of everolimus in combination with talazoparib (BMN673) compared with either drug alone. We further identified through microarray analysis and by rescue assays that mTOR inhibitors suppressed HR repair and synergized with PARP inhibitors through regulating the expression of SUV39H1 in BRCA-proficient TNBCs.
CONCLUSIONS: Collectively, these findings strongly suggest that combining mTOR inhibitors and PARP inhibitors would be an effective therapeutic approach to treat BRCA-proficient TNBC patients.

Liu X, Guo S, Liu X, Su L
Chaetocin induces endoplasmic reticulum stress response and leads to death receptor 5-dependent apoptosis in human non-small cell lung cancer cells.
Apoptosis. 2015; 20(11):1499-507 [PubMed] Related Publications
Epigenetic abnormalities are associated with non-small cell lung cancer (NSCLC) initiation and progression. Epigenetic drugs are being studied and in clinical trials. However, the molecular mechanism underlying the apoptosis by the epigenetic agents remains unclear. SUV39H1 is an important methyl-transferase for lysine 9 on histone H3 and usually related to gene transcriptional suppression, and chaetocin acts as the inhibitor of SUV39H1. We demonstrated here that chaetocin effectively suppressed the growth of multiple lung cancer cells through inducing apoptosis in a death receptor 5 (DR5)-dependent manner. Chaetocin treatment activated endoplasmic reticulum (ER) stress which gave rise to the up-regulation of ATF3 and CHOP. Furthermore, ATF3 and CHOP contributed to the induction of DR5 and subsequent apoptosis. When SUV39H1 was silenced with siRNA, the expression of ATF3, CHOP and DR5 was elevated. Thereafter, knockdown of SUV39H1 induced apoptosis in NSCLC cells. In summary, chaetocin pharmacologically inhibits the activity of SUV39H1 which provokes ER stress and results in up-regulation of ATF3 and CHOP, leading to DR5-dependent apoptosis eventually. These findings provide a novel interpretation on the anti-neoplastic activity of epigenetic drugs as a new therapeutic approach in NSCLC.

Wu D, Fu H, Zhou H, et al.
Effects of Novel ncRNA Molecules, p15-piRNAs, on the Methylation of DNA and Histone H3 of the CDKN2B Promoter Region in U937 Cells.
J Cell Biochem. 2015; 116(12):2744-54 [PubMed] Related Publications
Non-coding RNAs (ncRNAs) play key roles in epigenetic events. However, the exact mechanism of ncRNA guidance, particularly piwi-interacting RNAs (piRNAs), for the targeting of epigenetic regulatory factors to specific gene regions is unclear. Although piRNA function was first established in germ-line cells, piRNA may be crucial in cancer cells. This study investigated the potential roles of CDKN2B-related piRNA in leukemia cells to provide a potential tumorigenesis model of leukemia. CDKN2B-related piRNAs, hsa_piR_014637 and hsa_piR_011186 were transduced into the leukemia cell line U937 to study the effect of these two piRNAs on cell-cycle progression, apoptosis, heterochromatin formation, CDKN2B methylation and expression. Our results show that over-expressing hsa_piR_011186 promoted cell-cycle progression and decreased apoptosis. We also observed inhibition of CDKN2B gene expression. These effects were likely mediated by novel piRC (piRNA complex) of CDKN2B-related piRNA that associate with DNMT1, Suv39H1 and/or EZH2 proteins to modulate the methylation of DNA and histone H3 in the promoter region of the CDKN2B gene. The novel piRC complex facilitated epigenetic modifications on the promoter of cell-cycle regulating genes, providing an expanded view of the role of piRNA in the progression of leukemia cells.

Paschall AV, Yang D, Lu C, et al.
H3K9 Trimethylation Silences Fas Expression To Confer Colon Carcinoma Immune Escape and 5-Fluorouracil Chemoresistance.
J Immunol. 2015; 195(4):1868-82 [PubMed] Free Access to Full Article Related Publications
The Fas-FasL effector mechanism plays a key role in cancer immune surveillance by host T cells, but metastatic human colon carcinoma often uses silencing Fas expression as a mechanism of immune evasion. The molecular mechanism under FAS transcriptional silencing in human colon carcinoma is unknown. We performed genome-wide chromatin immunoprecipitation sequencing analysis and identified that the FAS promoter is enriched with H3K9me3 in metastatic human colon carcinoma cells. The H3K9me3 level in the FAS promoter region is significantly higher in metastatic than in primary cancer cells, and it is inversely correlated with Fas expression level. We discovered that verticillin A is a selective inhibitor of histone methyltransferases SUV39H1, SUV39H2, and G9a/GLP that exhibit redundant functions in H3K9 trimethylation and FAS transcriptional silencing. Genome-wide gene expression analysis identified FAS as one of the verticillin A target genes. Verticillin A treatment decreased H3K9me3 levels in the FAS promoter and restored Fas expression. Furthermore, verticillin A exhibited greater efficacy than decitabine and vorinostat in overcoming colon carcinoma resistance to FasL-induced apoptosis. Verticillin A also increased DR5 expression and overcame colon carcinoma resistance to DR5 agonist drozitumab-induced apoptosis. Interestingly, verticillin A overcame metastatic colon carcinoma resistance to 5-fluorouracil in vitro and in vivo. Using an orthotopic colon cancer mouse model, we demonstrated that tumor-infiltrating cytotoxic T lymphocytes are FasL(+) and that FasL-mediated cancer immune surveillance is essential for colon carcinoma growth control in vivo. Our findings determine that H3K9me3 of the FAS promoter is a dominant mechanism underlying FAS silencing and resultant colon carcinoma immune evasion and progression.

Park SJ, Shim JW, Park HS, et al.
MacroH2A1 downregulation enhances the stem-like properties of bladder cancer cells by transactivation of Lin28B.
Oncogene. 2016; 35(10):1292-301 [PubMed] Free Access to Full Article Related Publications
The histone variant, macroH2A1, has an important role in embryonic stem cell differentiation and tumor progression in various types of tumors. However, the regulatory roles of macroH2A1 on bladder cancer progression have not been fully elucidated. Here, we show that macroH2A1 knockdown promotes stem-like properties of bladder cancer cells. The knockdown of macroH2A1 in bladder cancer cells increased tumorigenicity, radioresistance, degeneration of reactive oxygen species, increased sphere formation capability and an increase in the proportion of side populations. We found that macroH2A1 is required for the suppression of Lin28B identified as a novel downstream target of macroH2A1 in bladder cancer. Loss of macroH2A1 expression significantly correlated with the elevated levels of Lin28B expression and subsequently inhibited the mature let-7 microRNA expression. Furthermore, the stable overexpression of Lin28B enhances the several phenotypes, including tumorigenicity and sphere-forming ability, which are induced by macroH2A1 depletion. Importantly, Lin28B expression was regulated by macroH2A1-mediated reciprocal binding of p300 and EZH2/SUV39H1. Our results suggest that Lin28B/let-7 pathway is tightly regulated by macroH2A1 and its cofactors, and have a pivotal role in the bladder tumor progression and the regulation of stem-like characteristics of bladder cancer cells.

Lai YS, Chen JY, Tsai HJ, et al.
The SUV39H1 inhibitor chaetocin induces differentiation and shows synergistic cytotoxicity with other epigenetic drugs in acute myeloid leukemia cells.
Blood Cancer J. 2015; 5:e313 [PubMed] Free Access to Full Article Related Publications
Epigenetic modifying enzymes have a crucial role in the pathogenesis of acute myeloid leukemia (AML). Methylation of lysine 9 on histone H3 by the methyltransferase G9a and SUV39H1 is associated with inhibition of tumor suppressor genes. We studied the effect of G9a and SUV39H1 inhibitors on viability and differentiation of AML cells and tested the cytotoxicity induced by combination of G9a and SUV39H1 inhibitors and various epigenetic drugs. The SUV39H1 inhibitor (chaetocin) and the G9a inhibitor (UNC0638) caused cell death in AML cells at high concentrations. However, only chaetocin-induced CD11b expression and differentiation of AML cells at non-cytotoxic concentration. HL-60 and KG-1a cells were more sensitive to chaetocin than U937 cells. Long-term incubation of chaetocin led to downregulation of SUV39H1 and reduction of H3K9 tri-methylation in HL-60 and KG-1a cells. Combination of chaetocin with suberoylanilide hydroxamic acid (SAHA, a histone deacetylase inhibitor) or JQ (a BET (bromodomain extra terminal) bromodomain inhibitor) showed synergistic cytotoxicity. Conversely, no synergism was found by combining chaetocin and UNC0638. More importantly, chaetocin-induced differentiation and combined cytotoxicity were also found in the primary cells of AML patients. Collectively, the SUV39H1 inhibitor chaetocin alone or in combination with other epigenetic drugs may be effective for the treatment of AML.

Liu X, Lei Q, Yu Z, et al.
MiR-101 reverses the hypomethylation of the LMO3 promoter in glioma cells.
Oncotarget. 2015; 6(10):7930-43 [PubMed] Free Access to Full Article Related Publications
LIM-only protein 3 (LMO3), a member of the LIM-only protein group, is a new DNA methylation gene that was identified in gliomas via the MeDIP-Chip in our previous study. In this study, we found that LIM-only protein 3 (LMO3) is hypomethylated and overexpressed in glioma cells and tissues. The overexpression of LMO3 was correlated with a poor prognosis in glioma patients, and LMO3 was indirectly inhibited by the tumor suppressor miR-101, which is a potential prognosis marker of gliomas. MiR-101 decreased the expression of LMO3 by reversing the methylation status of the LMO3 promoter and by inhibiting the presence of the methylation-related histones H3K4me2 and H3K27me3 and increasing the presence of H3K9me3 and H4K20me3 on the promoter. It was determined that miR-101 decreases the occupancy of H3K27me3 by inhibiting EZH2, DNMT3A and EED and decreases the H3K9me3 occupancy on the LMO3 promoter via SUV39H1, SUV39H2, G9a and PHF8. Furthermore, miR-101 suppresses the expression of LMO3 by decreasing USF and MZF1.

Petti E, Jordi F, Buemi V, et al.
Altered telomere homeostasis and resistance to skin carcinogenesis in Suv39h1 transgenic mice.
Cell Cycle. 2015; 14(9):1438-46 [PubMed] Free Access to Full Article Related Publications
The Suv39h1 and Suv39h2 H3K9 histone methyltransferases (HMTs) have a conserved role in the formation of constitutive heterochromatin and gene silencing. Using a transgenic mouse model system we demonstrate that elevated expression of Suv39h1 increases global H3K9me3 levels in vivo. More specifically, Suv39h1 overexpression enhances the imposition of H3K9me3 levels at constitutive heterochromatin at telomeric and major satellite repeats in primary mouse embryonic fibroblasts. Chromatin compaction is paralleled by telomere shortening, indicating that telomere length is controlled by H3K9me3 density at telomeres. We further show that increased Suv39h1 levels result in an impaired clonogenic potential of transgenic epidermal stem cells and Ras/E1A transduced transgenic primary mouse embryonic fibroblasts. Importantly, Suv39h1 overexpression in mice confers resistance to a DMBA/TPA induced skin carcinogenesis protocol that is characterized by the accumulation of activating H-ras mutations. Our results provide genetic evidence that Suv39h1 controls telomere homeostasis and mediates resistance to oncogenic stress in vivo. This identifies Suv39h1 as an interesting target to improve oncogene induced senescence in premalignant lesions.

Song TY, Lim J, Kim B, et al.
The role of tumor suppressor menin in IL-6 regulation in mouse islet tumor cells.
Biochem Biophys Res Commun. 2014; 451(2):308-13 [PubMed] Related Publications
Menin is a gene product of multiple endocrine neoplasia type1 (Men1), an inherited familial cancer syndrome characterized by tumors of endocrine tissues. To gain insight about how menin performs an endocrine cell-specific tumor suppressor function, we investigated the possibility that menin was integrated in a cancer-associated inflammatory pathway in a cell type-specific manner. Here, we showed that the expression of IL-6, a proinflammatory cytokine, was specifically elevated in mouse islet tumor cells upon depletion of menin and Men(-/-) MEF cells, but not in hepatocellular carcinoma cells. Histone H3 lysine (K) 9 methylation, but not H3 K27 or K4 methylation, was involved in menin-dependent IL-6 regulation. Menin occupied the IL-6 promoter and recruited SUV39H1 to induce H3 K9 methylation. Our findings provide a molecular insight that menin-dependent induction of H3 K9 methylation in the cancer-associated interleukin gene might be linked to preventing endocrine-specific tumorigenesis.

Chiba T, Saito T, Yuki K, et al.
Histone lysine methyltransferase SUV39H1 is a potent target for epigenetic therapy of hepatocellular carcinoma.
Int J Cancer. 2015; 136(2):289-98 [PubMed] Related Publications
Histone H3 lysine 9 trimethylation (H3K9me3) is associated with transcriptional repression and regulated by histone lysine methyltransferases such as SUV39H1 and ESET. However, the functional roles of these enzymes in hepatocellular carcinoma (HCC) remain uncertain. In this study, we conducted loss-of-function assays for HCC cells. SUV39H1 knockdown but not ESET knockdown reduced H3K9me3 levels and impaired HCC cell growth and sphere formation. The pharmacological inhibition of SUV39H1 by chaetocin resulted in cell growth inhibition and inducing cellular apoptosis in culture and xenograft subcutaneous tumors. Real-time polymerase chain reaction analysis indicated high levels of SUV39H1 expression in 24 of 42 (57.1%) HCC surgical samples compared with corresponding nontumor tissues. Immunohistochemistry identified high levels of H3K9me3 and ESET proteins in 23 (54.8%) and 29 (69.0%) tumor tissues, respectively. However, these proteins' expressions were only observed in biliary epithelial cells and periportal hepatocytes of nontumor tissues. Expression levels of SUV39H1 but not those of ESET were significantly correlated with H3K9me3 levels. The cumulative HCC recurrence rate was significantly higher for patients with elevated SUV39H1 expression and H3K9me3 levels. In conclusion, our data indicate that elevated SUV39H1 expression and high levels of H3K9me3 have important roles in HCC development and progression. Therefore, the pharmacological inhibition of SUV39H1 may be a promising therapeutic approach for HCC treatment.

Cai L, Ma X, Huang Y, et al.
Aberrant histone methylation and the effect of Suv39H1 siRNA on gastric carcinoma.
Oncol Rep. 2014; 31(6):2593-600 [PubMed] Related Publications
The present study aimed to investigate the involvement of the Suv39H1 histone methyltransferase in the epigenetic changes in the euchromatic promoter in gastric carcinoma. We retrospectively analyzed the protein of Suv39H1 and tri-methylated histone H3 lysine 9 (H3K9) and histone H3 lysine 4 (H3K4) in 175 cases of gastric carcinoma by immunohistochemistry. Suv39H1 was depleted by siRNA, and cell apoptosis and cell proliferation were assessed by TUNEL and MTT assays, respectively. Histone methylated H3K9 and histone acetylated H3 and H4 were evaluated by western blotting. We found that the expression of Suv39H1 and tri-methylated H3K9 in gastric carcinoma was higher than that in benign gastric diseases (p<0.05). Tri-methylated H3K4 was similar in both tissue types (p>0.05). Both Suv39H1 and tri-methylated H3K9 were positively correlated with the degree of differentiation, depth of infiltration and lymphatic invasion (p<0.05) in gastric carcinoma. In addition, tri-methylated H3K9 was positively correlated with tumor stage, and node and metastatic statuses (p<0.05). Activation of Suv39H1 and overexpression of H3K9 tri-methylation may play an important role in tumorigenesis. They may be useful as a predictor for poor prognosis in gastric carcinoma. Silencing of the Suv39H1 gene decreased tri-methylated H3K9 and increased histone H3 acetylation, which caused activation of gene transcription, while there was no change in histone H4 acetylation. Depletion of Suv39H1 induced apoptosis and inhibited cell proliferation in the gastric cancer MGC803 cell line, while decreasing BCL-2, pro-caspase-9, pro-caspase-3 and C-myc. Suv39H1 may be a potential gene target for anti-gastric carcinoma therapy.

Noh HJ, Kim KA, Kim KC
p53 down-regulates SETDB1 gene expression during paclitaxel induced-cell death.
Biochem Biophys Res Commun. 2014; 446(1):43-8 [PubMed] Related Publications
Paclitaxel (PTX) is a chemotherapeutic drug which induces tubulin stability and regulates expression of death related genes in human cancer cells. Its anticancer mechanism is well known, however its effects on chromatin remodeling factors are poorly understood. In this study, we examine if PTX affects expression of SETDB1 HMTase during cell death. PTX induces cell death via G2/M arrest in human lung cancer cells. PTX treatment induces the p53 protein, but down-regulates expression of SETDB1 at the transcriptional level as well as the protein level. SETDB1 promoter activity is increased to approximately 30-fold in normal condition, but the activity is significantly inhibited in the PTX treated group. In addition, p53 transfection inhibits SETDB1 promoter activity. The p53 protein directly binds to proximal region of the SETDB1 promoter, and H3K9me3 occupancy in this region also increased in the presence of p53. Immunoprecipitation experiment showed interaction of p53 and SUV39H1, suggesting that association of p53 and SUV39H1 is responsible for increased H3K9me3 occupancy and transcription repression of SETDB1. This result demonstrates that PTX down-regulates SETDB1 gene expression in a p53 dependent manner, and p53 might participate in heterochromatic repression on the promoter regions of SETDB1.

Barh D, Jain N, Tiwari S, et al.
A novel in silico reverse-transcriptomics-based identification and blood-based validation of a panel of sub-type specific biomarkers in lung cancer.
BMC Genomics. 2013; 14 Suppl 6:S5 [PubMed] Free Access to Full Article Related Publications
Lung cancer accounts for the highest number of cancer-related deaths worldwide. Early diagnosis significantly increases the disease-free survival rate and a large amount of effort has been expended in screening trials and the development of early molecular diagnostics. However, a gold standard diagnostic strategy is not yet available. Here, based on miRNA expression profile in lung cancer and using a novel in silico reverse-transcriptomics approach, followed by analysis of the interactome; we have identified potential transcription factor (TF) markers that would facilitate diagnosis of subtype specific lung cancer. A subset of seven TF markers has been used in a microarray screen and was then validated by blood-based qPCR using stage-II and IV non-small cell lung carcinomas (NSCLC). Our results suggest that overexpression of HMGA1, E2F6, IRF1, and TFDP1 and downregulation or no expression of SUV39H1, RBL1, and HNRPD in blood is suitable for diagnosis of lung adenocarcinoma and squamous cell carcinoma sub-types of NSCLC. Here, E2F6 was, for the first time, found to be upregulated in NSCLC blood samples. The miRNA-TF-miRNA interaction based molecular mechanisms of these seven markers in NSCLC revealed that HMGA1 and TFDP1 play vital roles in lung cancer tumorigenesis. The strategy developed in this work is applicable to any other cancer or disease and can assist in the identification of potential biomarkers.

Yu X, Shahir AM, Sha J, et al.
Short-chain fatty acids from periodontal pathogens suppress histone deacetylases, EZH2, and SUV39H1 to promote Kaposi's sarcoma-associated herpesvirus replication.
J Virol. 2014; 88(8):4466-79 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Periodontal pathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum produce five different short-chain fatty acids (SCFAs) as metabolic by-products. We detect significantly higher levels of SCFAs in the saliva of patients with severe periodontal disease. The different SCFAs stimulate lytic gene expression of Kaposi's sarcoma-associated herpesvirus (KSHV) dose dependently and synergistically. SCFAs inhibit class-1/2 histone deacetylases (HDACs) and downregulate expression of silent information regulator-1 (SIRT1). SCFAs also downregulate expression of enhancer of zeste homolog2 (EZH2) and suppressor of variegation 3-9 homolog1 (SUV39H1), which are two histone N-lysine methyltransferases (HLMTs). By suppressing the different components of host epigenetic regulatory machinery, SCFAs increase histone acetylation and decrease repressive histone trimethylations to transactivate the viral chromatin. These new findings provide mechanistic support that SCFAs from periodontal pathogens stimulate KSHV replication and infection in the oral cavity and are potential risk factors for development of oral Kaposi's sarcoma (KS).
IMPORTANCE: About 20% of KS patients develop KS lesions first in the oral cavity, while other patients never develop oral KS. It is not known if the oral microenvironment plays a role in oral KS tumor development. In this work, we demonstrate that a group of metabolic by-products, namely, short-chain fatty acids, from bacteria that cause periodontal disease promote lytic replication of KSHV, the etiological agent associated with KS. These new findings provide mechanistic support that periodontal pathogens create a unique microenvironment in the oral cavity that contributes to KSHV replication and development of oral KS.

Yang Y, Liu R, Qiu R, et al.
CRL4B promotes tumorigenesis by coordinating with SUV39H1/HP1/DNMT3A in DNA methylation-based epigenetic silencing.
Oncogene. 2015; 34(1):104-18 [PubMed] Related Publications
Cullin 4B (CUL4B) is a component of the Cullin4B-Ring E3 ligase complex (CRL4B) that functions in proteolysis and is implicated in tumorigenesis. Here, we report that CRL4B is associated with histone methyltransferase SUV39H1, heterochromatin protein 1 (HP1) and DNA methyltransferases 3A (DNMT3A). We showed that CRL4B, through catalyzing H2AK119 monoubiquitination, facilitates H3K9 tri-methylation and DNA methylation, two key epigenetic modifications involved in DNA methylation-based gene silencing. Depletion of CUL4B resulted in loss of not only H2AK119 monoubiquitination but also H3K9 trimethylation and DNA methylation, leading to derepression of a collection of genes, including the tumor suppressor IGFBP3. We demonstrated that CUL4B promotes cell proliferation and invasion, which are consistent with a tumorigenic phenotype, at least partially by repressing IGFBP3. We found that the expression of CUL4B is markedly upregulated in samples of human cervical carcinoma and is negatively correlated with the expression of IGFBP3. Our experiments unveiled a coordinated action between histone ubiquitination/methylation and DNA methylation in transcription repression, providing a mechanism for CUL4B in tumorigenesis.

Lee MC, Kuo YY, Chou WC, et al.
Gfi-1 is the transcriptional repressor of SOCS1 in acute myeloid leukemia cells.
J Leukoc Biol. 2014; 95(1):105-15 [PubMed] Related Publications
Silencing of SOCS1, a TSG, has been detected in various malignancies, including AML. However, the underlying mechanism of SOCS1 inactivation remains elusive. In this study, we explored the role of histone methylation in SOCS1 expression in AML cells. By ChIP assay, we demonstrated that G9a and SUV39H1, two enzymes catalyzing H3K9 methylation, were physically associated with the SOCS1 promoter, and treatment with chaetocin, a histone methyltransferase inhibitor, suppressed H3K9 methylation on the SOCS1 promoter and enhanced SOCS1 expression. Furthermore, knockdown of G9a and SUV39H1 by siRNA could also induce SOCS1 expression. On the other hand, SOCS1 knockdown by shRNA eliminated chaetocin-induced cell apoptosis. To investigate further whether any transcription factor was involved in H3K9 methylation-related SOCS1 repression, we scanned the sequences of the SOCS1 gene promoter and found two binding sites for Gfi-1, a transcription repressor. By DNA pull-down and ChIP assays, we showed that Gfi-1 directly bound the SOCS1 promoter, and ectopic Gfi-1 expression suppressed STAT5-induced SOCS1 promoter activation. In contrast, Gfi-1 knockdown by shRNA enhanced SOCS1 expression and inhibited STAT5 expression. Moreover, the knockdown of G9a completely rescued the repressive effect of Gfi-1 on STAT5A-induced SOCS1 promoter activation. Collectively, our study indicates that the expression of Gfi-1 contributes to SOCS1 silencing in AML cells through epigenetic modification, and suppression of histone methyltransferase can provide new insight in AML therapy.

Spyropoulou A, Gargalionis A, Dalagiorgou G, et al.
Role of histone lysine methyltransferases SUV39H1 and SETDB1 in gliomagenesis: modulation of cell proliferation, migration, and colony formation.
Neuromolecular Med. 2014; 16(1):70-82 [PubMed] Related Publications
Posttranslational modifications of histones are considered as critical regulators of gene expression, playing significant role in the pathogenesis and progression of tumors. Trimethylation of histone 3 lysine 9 (H3K9me3), a repressed transcription mark, is mainly regulated by the histone lysine N-methyltransferases (HKMTs), SUV39H1 and SETDB1. The present study investigated the implication of these HKMTs in glioma progression. SUV39H1 and SETDB1 expression was upregulated in glioma cell lines (GOS-3, 1321N1, T98G, U87MG) and in glioma tissues compared to normal brain being positively correlated with grade and histological malignancy. Suppression by siRNA of the two HKMTs for 24 and 48 h resulted in significantly reduced proliferation of GOS-3 and T98G glioma cells with siSUV39H1 effects been most prominent. Furthermore, HKMTs knockdown-induced apoptosis with a high rate of apoptotic cells have been observed after siSUV39H1 and siSETDB1 for both cell lines. Additionally, suppression of the two HKMTs reduced cell migration and clonogenic ability of both glioma cell lines. Our results indicate overexpression of SETDB1 and SUV39H1 in gliomas. Treatments that alter HKMT expression affect the proliferative and apoptotic rates in glioma cells as well as their migratory and colony formation capacity. These data suggest that both HKMTs and especially SUV39H1 may serve as novel biomarkers for future therapeutic targeting of these tumors.

Lee JK, Kim KC
DZNep, inhibitor of S-adenosylhomocysteine hydrolase, down-regulates expression of SETDB1 H3K9me3 HMTase in human lung cancer cells.
Biochem Biophys Res Commun. 2013; 438(4):647-52 [PubMed] Related Publications
3-Deazaneplanocin A (DZNep), an epigenetic anticancer drug, leads to the indirect suppression of S-adenosyl methionine-dependent cellular methylations by inhibiting S-adenosyl homocystein (AdoHcy) hydrolase. Although it is well known that DZNep targets the degradation of EZH2 protein, H3K27me3 HMTase, there are still uncertainties about the regulation of other types of HMTases during cell death. In this study, we describe that SETDB1 gene expression was regulated by DZNep treatment in human lung cancer cells. We confirm that DZNep induced growth inhibition and increased the dead cell population of lung cancer cells. DZNep treatment affected histone methylations, including H3K27me3 and H3K9me3, but not H3K4me3. Reduced levels of H3K27me3 and H3K9me3 were related with the decreased EZH2 and SETDB1 proteins. Real time PCR analysis showed that SETDB1 gene expression was decreased by DZNep treatment, but no effect was observed for EZH2 gene expression. We cloned the promoter region of SETDB1 and SUV39H1 genes, and performed luciferase assays. The promoter activity of SETDB1 gene was down regulated by DZNep treatment, whereas no effect on SUV39H1 promoter activity was observed. In conclusion, we suggest that DZNep regulates not only on H3K27me3 HMTase EZH2, but also H3K9 HMTase SETDB1 gene expression at the transcription level, implicating that the mechanism of action of DZNep targets multiple HMTases during the death of lung cancer cells.

Thakker RV
Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4).
Mol Cell Endocrinol. 2014; 386(1-2):2-15 [PubMed] Free Access to Full Article Related Publications
Multiple endocrine neoplasia (MEN) is characterized by the occurrence of tumors involving two or more endocrine glands within a single patient. Four major forms of MEN, which are autosomal dominant disorders, are recognized and referred to as: MEN type 1 (MEN1), due to menin mutations; MEN2 (previously MEN2A) due to mutations of a tyrosine kinase receptor encoded by the rearranged during transfection (RET) protoncogene; MEN3 (previously MEN2B) due to RET mutations; and MEN4 due to cyclin-dependent kinase inhibitor (CDNK1B) mutations. Each MEN type is associated with the occurrence of specific tumors. Thus, MEN1 is characterized by the occurrence of parathyroid, pancreatic islet and anterior pituitary tumors; MEN2 is characterized by the occurrence of medullary thyroid carcinoma (MTC) in association with phaeochromocytoma and parathyroid tumors; MEN3 is characterized by the occurrence of MTC and phaeochromocytoma in association with a marfanoid habitus, mucosal neuromas, medullated corneal fibers and intestinal autonomic ganglion dysfunction, leading to megacolon; and MEN4, which is also referred to as MENX, is characterized by the occurrence of parathyroid and anterior pituitary tumors in possible association with tumors of the adrenals, kidneys, and reproductive organs. This review will focus on the clinical and molecular details of the MEN1 and MEN4 syndromes. The gene causing MEN1 is located on chromosome 11q13, and encodes a 610 amino-acid protein, menin, which has functions in cell division, genome stability, and transcription regulation. Menin, which acts as scaffold protein, may increase or decrease gene expression by epigenetic regulation of gene expression via histone methylation. Thus, menin by forming a subunit of the mixed lineage leukemia (MLL) complexes that trimethylate histone H3 at lysine 4 (H3K4), facilitates activation of transcriptional activity in target genes such as cyclin-dependent kinase (CDK) inhibitors; and by interacting with the suppressor of variegation 3-9 homolog family protein (SUV39H1) to mediate H3K methylation, thereby silencing transcriptional activity of target genes. MEN1-associated tumors harbor germline and somatic mutations, consistent with Knudson's two-hit hypothesis. Genetic diagnosis to identify individuals with germline MEN1 mutations has facilitated appropriate targeting of clinical, biochemical and radiological screening for this high risk group of patients for whom earlier implementation of treatments can then be considered. MEN4 is caused by heterozygous mutations of CDNK1B which encodes the 196 amino-acid CDK1 p27Kip1, which is activated by H3K4 methylation.

Lin Y, Dong C, Zhou BP
Epigenetic regulation of EMT: the Snail story.
Curr Pharm Des. 2014; 20(11):1698-705 [PubMed] Free Access to Full Article Related Publications
While the epithelial-mesenchymal transition (EMT) plays a fundamental role during development, its deregulation can adversely promote tumor metastasis. The phenotypic and cellular plasticity of EMT indicates that it is subject to epigenetic regulation. A hallmark of EMT is E-cadherin suppression. In this review, we try to embrace recent findings on the transcription factor Snail-mediated epigenetic silencing of E-cadherin. Our studies as well as those of others independently demonstrated that Snail can recruit various epigenetic machineries to the E-cadherin promoter. Based on these results, we propose a model of epigenetic regulation of EMT governed by Snail. Briefly, recruitment of the LSD1/HDAC complex by Snail facilitates histone H3K4 demethylation and H3/H4 deacetylation. Histone deacetylation may promote subsequent recruitment of PRC2 to methylate H3K27, while H3K4 demethylation favors the association of H3K9 methyltransferases G9a and Suv39H1. Finally, DNA methyltransferases (DNMTs) can be recruited to the promoter area in a G9a/Suv39H1-dependent manner. Together, these chromatin-modifying enzymes function in a Snail-mediated, highly orchestrated fashion to suppress E-cadherin. Disruption of the connection between Snail and these epigenetic machineries may represent an efficient strategy for the treatment of EMT-related diseases, including tumor metastasis.

Black JC, Manning AL, Van Rechem C, et al.
KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors.
Cell. 2013; 154(3):541-55 [PubMed] Free Access to Full Article Related Publications
Acquired chromosomal instability and copy number alterations are hallmarks of cancer. Enzymes capable of promoting site-specific copy number changes have yet to be identified. Here, we demonstrate that H3K9/36me3 lysine demethylase KDM4A/JMJD2A overexpression leads to localized copy gain of 1q12, 1q21, and Xq13.1 without global chromosome instability. KDM4A-amplified tumors have increased copy gains for these same regions. 1q12h copy gain occurs within a single cell cycle, requires S phase, and is not stable but is regenerated each cell division. Sites with increased copy number are rereplicated and have increased KDM4A, MCM, and DNA polymerase occupancy. Suv39h1/KMT1A or HP1γ overexpression suppresses the copy gain, whereas H3K9/K36 methylation interference promotes gain. Our results demonstrate that overexpression of a chromatin modifier results in site-specific copy gains. This begins to establish how copy number changes could originate during tumorigenesis and demonstrates that transient overexpression of specific chromatin modulators could promote these events.

Albacker CE, Storer NY, Langdon EM, et al.
The histone methyltransferase SUV39H1 suppresses embryonal rhabdomyosarcoma formation in zebrafish.
PLoS One. 2013; 8(5):e64969 [PubMed] Free Access to Full Article Related Publications
Epigenetics, or the reversible and heritable marks of gene regulation not including DNA sequence, encompasses chromatin modifications on both the DNA and histones and is as important as the DNA sequence itself. Chromatin-modifying factors are playing an increasingly important role in tumorigenesis, particularly among pediatric rhabdomyosarcomas (RMS), revealing potential novel therapeutic targets. We performed an overexpression screen of chromatin-modifying factors in a KRAS(G12D)-driven zebrafish model for RMS. Here, we describe the identification of a histone H3 lysine 9 histone methyltransferase, SUV39H1, as a suppressor of embryonal RMS formation in zebrafish. This suppression is specific to the histone methyltransferase activity of SUV39H1, as point mutations in the SET domain lacked the effect. SUV39H1-overexpressing and control tumors have a similar proliferation rate, muscle differentiation state, and tumor growth rate. Strikingly, SUV39H1-overexpressing fish initiate fewer tumors, which results in the observed suppressive phenotype. We demonstrate that the delayed tumor onset occurs between 5 and 7 days post fertilization. Gene expression profiling at these stages revealed that in the context of KRAS(G12D) overexpression, SUV39H1 may suppress cell cycle progression. Our studies provide evidence for the role of SUV39H1 as a tumor suppressor.

Song K, Han C, Zhang J, et al.
Epigenetic regulation of MicroRNA-122 by peroxisome proliferator activated receptor-gamma and hepatitis b virus X protein in hepatocellular carcinoma cells.
Hepatology. 2013; 58(5):1681-92 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: MicroRNA-122 (miR-122), a pivotal liver-specific miRNA, has been implicated in several liver diseases including hepatocellular carcinoma (HCC) and hepatitis C and B viral infection. This study aimed to explore epigenetic regulation of miR-122 in human HCC cells and to examine the effect of hepatitis C virus (HCV) and hepatitis B virus (HBV). We performed microRNA microarray analysis and identified miR-122 as the most up-regulated miRNA (6-fold) in human HCC cells treated with 5'aza-2'deoxycytidine (5-Aza-CdR, DNA methylation inhibitor) and 4-phenylbutyric acid (PBA, histone deacetylation inhibitor). Real-time polymerase chain reaction (PCR) analysis verified significant up-regulation of miR-122 by 5'aza and PBA in HCC cells, and to a lesser extent in primary hepatocytes. Peroxisome proliferator activated receptor-gamma (PPARγ) and retinoid X receptor alpha (RXRα) complex was found to be associated with the DR1 and DR2 consensus site in the miR-122 gene promoter which enhanced miR-122 gene transcription. 5-Aza-CdR and PBA treatment increased the association of PPARγ/RXRα, but decreased the association of its corepressors (N-CoR and SMRT), with the miR-122 DR1 and DR2 motifs. The aforementioned DNA-protein complex also contains SUV39H1, an H3K9 histone methyl transferase, which down-regulates miR-122 expression.
CONCLUSIONS: These findings establish a novel role of the PPARγ binding complex for epigenetic regulation of miR-122 in human HCC cells. Moreover, we show that hepatitis B virus X protein binds PPARγ and inhibits the transcription of miR-122, whereas hepatitis C viral particles exhibited no significant effect; these findings provide mechanistic insight into reduction of miR-122 in patients with HBV but not with HCV infection.

Yang YJ, Song TY, Park J, et al.
Menin mediates epigenetic regulation via histone H3 lysine 9 methylation.
Cell Death Dis. 2013; 4:e583 [PubMed] Free Access to Full Article Related Publications
Menin, encoded by the multiple endocrine neoplasia type 1 (MEN1) gene, is a tumor suppressor that leads to multiple endocrine tumors upon loss of its function. Menin functions as a transcriptional activator by tethering MLL complex to mediate histone H3 K4 methylation. It also functions as a repressor. However, the molecular mechanism of how menin contributes to the opposite outcome in gene expression is largely unknown. Here, we investigated the role of menin in the epigenetic regulation of transcription mediated by histone covalent modification. We show that the global methylation level of histone H3 K9, as well as H3 K4, was decreased in Men1(-/-) MEF cells. Consistently, menin was able to interact with the suppressor of variegation 3-9 homolog family protein, SUV39H1, to mediate H3 K9 methylation. This interaction decreased when patient-derived MEN1 mutation was introduced into the SUV39H1-interaction domain. We show that menin mediated different chromatin changes depending on target genes. Chromatin immunoprecipitation studies showed that menin directly associated with the GBX2 promoter and menin-dependent recruitment of SUV39H1 was essential for chromatin remodeling and transcriptional regulation. These results provide a molecular basis of how menin functions as a transcriptional repressor and suggest that menin-dependent integration of H3 K9 methylation might play an important role in preventing tumors.

Chen JH, Yeh KT, Yang YM, et al.
High expressions of histone methylation- and phosphorylation-related proteins are associated with prognosis of oral squamous cell carcinoma in male population of Taiwan.
Med Oncol. 2013; 30(2):513 [PubMed] Related Publications
Since 2008, oral squamous cell carcinoma (OSCC) has climbed to the fourth place in cancer mortality in the male population of Taiwan. Epigenetic regulations including DNA methylation and histone modification control gene expression and play important roles during cancer progression. Since the relationship between histone modification and prognosis of OSCC is inconclusive, we collected 215 formalin-fixed and paraffin-embedded tissues from male patients having OSCC and surveyed them by tissue microarray-based immunohistochemical staining. The association between five histone modification-related genes, clinicopathological parameters, and prognosis of OSCC was examined. From tissue microarray immunohistochemistry staining results, we found that the nuclear staining intensity of ARK2 (Aurora kinase B-a serine/threonine-protein kinase of H3S10) was associated with poor clinical outcomes (≤3-year survival, p = 0.005). The cytosolic staining intensity of the ARK2 protein was associated with tumor stage (p = 0.006) and tumor size (T) of TNM staging system (p = 0.026). Cytoplasmic staining intensity of G9a (H3K9 methyltransferase) was associated with histological grade of differentiation (p = 0.026). EZH2 (H3K27 methyltransferase) and SUV39H1 (H3K9 methyltransferase) overexpressions in nuclei were, respectively, associated with lymph node metastasis (N, p = 0.016) and stage (p = 0.009). Our result suggests that overexpressions of histone modification-related proteins-ARK2, G9a, EZH2, and SUV39H1 but not SUV39H2 are associated with prognosis of OSCC in the male population of Taiwan. These proteins, especially ARK2, may serve as effective prognostic factors and can also be used as biomarkers for predicting various clinical outcomes of OSCCs in the Taiwanese population.

Tran HT, Kim HN, Lee IK, et al.
Improved therapeutic effect against leukemia by a combination of the histone methyltransferase inhibitor chaetocin and the histone deacetylase inhibitor trichostatin A.
J Korean Med Sci. 2013; 28(2):237-46 [PubMed] Free Access to Full Article Related Publications
SUV39H1 is a histone 3 lysine 9 (H3K9)-specific methyltransferase that is important for heterochromatin formation and the regulation of gene expression. Chaetocin specifically inhibits SUV39H1, resulted in H3K9 methylation reduction as well as reactivation of silenced genes in cancer cells. Histone deacetylase (HDAC) inhibitors inhibit deacetylases and accumulate high levels of acetylation lead to cell cycle arrest and apoptosis. In this study, we demonstrated that treatment with chaetocin enhanced apoptosis in human leukemia HL60, KG1, Kasumi, K562, and THP1 cells. In addition, chaetocin induced the expression of cyclin-dependent kinase inhibitor 2B (p15), E-cadherin (CDH1) and frizzled family receptor 9 (FZD9) through depletion of SUV39H1 and reduced H3K9 methylation in their promoters. Co-treatment with chaetocin and HDAC inhibitor trichostatin A (TSA) dramatically increased apoptosis and produced greater activation of genes. Furthermore, this combined treatment significantly increased loss of SUV39H1 and reduced histone H3K9 trimethylation responses accompanied by increased acetylation. Importantly, co-treatment with chaetocin and TSA produced potent antileukemic effects in leukemia cells derived from patients. These in vitro findings suggest that combination therapy with SUV39H1 and HDAC inhibitors may be of potential value in the treatment of leukemia.

Dong C, Wu Y, Wang Y, et al.
Interaction with Suv39H1 is critical for Snail-mediated E-cadherin repression in breast cancer.
Oncogene. 2013; 32(11):1351-62 [PubMed] Free Access to Full Article Related Publications
Expression of E-cadherin, a hallmark of epithelial-mesenchymal transition (EMT), is often lost due to promoter DNA methylation in basal-like breast cancer (BLBC), which contributes to the metastatic advantage of this disease; however, the underlying mechanism remains unclear. Here, we identified that Snail interacted with Suv39H1 (suppressor of variegation 3-9 homolog 1), a major methyltransferase responsible for H3K9me3 that intimately links to DNA methylation. We demonstrated that the SNAG domain of Snail and the SET domain of Suv39H1 were required for their mutual interactions. We found that H3K9me3 and DNA methylation on the E-cadherin promoter were higher in BLBC cell lines. We showed that Snail interacted with Suv39H1 and recruited it to the E-cadherin promoter for transcriptional repression. Knockdown of Suv39H1 restored E-cadherin expression by blocking H3K9me3 and DNA methylation and resulted in the inhibition of cell migration, invasion and metastasis of BLBC. Our study not only reveals a critical mechanism underlying the epigenetic regulation of EMT, but also paves a way for the development of new treatment strategies against this disease.

Babbio F, Pistore C, Curti L, et al.
The SRA protein UHRF1 promotes epigenetic crosstalks and is involved in prostate cancer progression.
Oncogene. 2012; 31(46):4878-87 [PubMed] Related Publications
Epigenetic silencing of tumour suppressor genes is an important mechanism involved in cell transformation and tumour progression. The Set and RING-finger-associated domain-containing protein UHRF1 might be an important link between different epigenetic pathways. Here, we report that UHRF1 is frequently overexpressed in human prostate tumours and has an important role in prostate cancer pathogenesis and progression. Analysis of human prostate cancer samples by microarrays and immunohistochemistry showed increased expression of UHRF1 in about half of the cases. Moreover, UHRF1 expression was associated with reduced overall survival after prostatectomy in patients with organ-confined prostate tumours (P < 0.0001). UHRF1 expression was negatively correlated with several tumour suppressor genes and positively with the histone methyltransferase (HMT) EZH2 both in prostate tumours and cell lines. UHRF1 knockdown reduced proliferation, clonogenic capability and anchorage-independent growth of prostate cancer cells. Depletion of UHRF1 resulted in reactivation of several tumour suppressor genes. Gene reactivation upon UHRF1 depletion was associated with changes in histone H3K9 methylation, acetylation and DNA methylation, and impaired binding of the H3K9 HMT Suv39H1 to the promoter of silenced genes. Co-immunoprecipitation experiments showed direct interaction between UHRF1 and Suv39H1. Our data support the notion that UHRF1, along with Suv39H1 and DNA methyltransferases, contributes to epigenetic gene silencing in prostate tumours. This could represent a parallel and convergent pathway to the H3K27 methylation catalyzed by EZH2 to synergistically promote inactivation of tumour suppressor genes. Deregulated expression of UHRF1 is involved in the prostate cancer pathogenesis and might represent a useful marker to distinguish indolent cancer from those at high risk of lethal progression.

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