Research IndicatorsGraph generated 31 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (8)
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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: KDM5A (cancer-related)
Paroni G, Bolis M, Zanetti A, et al.HER2-positive breast-cancer cell lines are sensitive to KDM5 inhibition: definition of a gene-expression model for the selection of sensitive cases.
Oncogene. 2019; 38(15):2675-2689 [PubMed
] Related Publications
Targeting of histone methylation has therapeutic potential in oncology. Here, we provide proof-of-principle that pharmacological inhibition of KDM5 histone-demethylases is a new strategy for the personalized treatment of HER2
Plch J, Hrabeta J, Eckschlager TKDM5 demethylases and their role in cancer cell chemoresistance.
Int J Cancer. 2019; 144(2):221-231 [PubMed
] Related Publications
Histone methylation is important in the regulation of genes expression, and thus its dysregulation has been observed in various cancers. KDM5 enzymes are capable of removing tri- and di- methyl marks from lysine 4 on histone H3 (H3K4) which makes them potential players in the downregulation of tumor suppressors, but could also suggest that their activity repress oncogenes. Depending on the methylation site, their effect on transcription can be either activating or repressing. There is emerging evidence for deregulation of KDM5A/B/C/D and important phenotypic consequences in various types of cancer. It has been suggested that the KDM5 family of demethylases plays a role in the appearance of drug tolerance. Drug resistance remains a challenge to successful cancer treatment. This review summarizes recent advances in understanding the functions of KDM5 histone demethylases in cancer chemoresistance and potential therapeutic targeting of these enzymes, which seems to prevent the emergence of a drug-resistant population.
Ham J, Lee S, Lee H, et al.Genome-Wide Methylation Analysis Identifies NOX4 and KDM5A as Key Regulators in Inhibiting Breast Cancer Cell Proliferation by Ginsenoside Rg3.
Am J Chin Med. 2018; 46(6):1333-1355 [PubMed
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Ginsenoside Rg3 is a key metabolite of ginseng and is known to inhibit cancer cell growth. However, the epigenetics of CpG methylation and its regulatory mechanism have yet to be determined. Genome-wide methylation analysis of MCF-7 breast cancer cells treated with Rg3 was performed to identify epigenetically regulated genes and pathways. The effect of Rg3 on apoptosis and cell proliferation was examined by a colony formation assay and a dye-based cell proliferation assay. The association between methylation and gene expression was monitored by RT-PCR and Western blot analysis. Genome-wide methylation analysis identified the "cell morphology"-related pathway as the top network. Rg3 induced late stage apoptosis but inhibited cell proliferation up to 60%. Hypermethylated TRMT1L, PSMC6 and NOX4 were downregulated by Rg3, while hypomethylated ST3GAL4, RNLS and KDM5A were upregulated. In accordance, downregulation of NOX4 by siRNA abrogated the cell growth effect of Rg3, while the effect was opposite for KDM5A. Notably, breast cancer patients with a higher expression of NOX4 and KDM5A showed poor and good prognosis of survival, respectively. In conclusion, Rg3 deregulated tumor-related genes through alteration of the epigenetic methylation level leading to growth inhibition of cancer cells.
Shokri G, Doudi S, Fathi-Roudsari M, et al.Targeting histone demethylases KDM5A and KDM5B in AML cancer cells: A comparative view.
Leuk Res. 2018; 68:105-111 [PubMed
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Epigenetic modifications play an important role in initiation and progression of cancers including acute myeloid leukemia. Among different epigenetic modifiers, lysine specific demethylases have been noticed as potential therapeutic targets. KDM5 family of histone demethylases which removes methyl marks from lysine residues of H3, are frequently found in the promoter region of transcriptionally active genes resulting in repression of expression. Here we have compared the effects of KDM5A and KDM5B downregulation on HL-60 cell line behavior. KDM5A/5B knockdown resulted in lower viability of HL-60 cells in addition to modified cell cycle distribution and sub-G1 accumulation. Induction of apoptosis was observed in both knockdown cells. But in spite of similarity in their role, downregulation of KDM5A showed more efficient anti-leukemic effects in comparison to KDM5B. Cells showed higher accumulation in sub-G1 and apoptosis occurred significantly higher and also earlier after KDM5A reduction. Expression analysis confirmed almost 5 and 4 fold increased expression for bax and caspase-3 after downregulation of KDM5A in comparison to KDM5B. Due to the present study we propose KDM5A as a potential target for therapeutic aspects of acute myeloid leukemia although further investigations are needed.
BACKGROUND: Esophageal sarcomatoid carcinoma (ESC) is a rare disease with a mixture of both carcinomatous and sarcomatous components in the tumor. Its genetic background and mechanisms of oncogenesis remain largely unknown.
METHODS: Here we performed targeted next generation sequencing (NGS) on a pan-cancer gene panel in 15 ESC tumors to explore their genetic alterations, and aimed to identify clinically actionable mutations for future treatment instructions.
RESULTS: TP53 alterations were identified in all patients. Alterations in receptor tyrosine kinases (RTK) were identified in 10 out of 15 patients. Members of downstream RAS and PI3-kinase pathways are also mutated in 10 patients, and PIK3CA is the top mutated gene in these pathways. In addition, we identified mutations on histone modification genes in 5 patients, including histone acetyltransferase gene EP300 and its homologue CREBBP, lysine methyltransferase genes KMT2A and KMT2B, and lysine demethylase gene KDM5A. Finally, mismatch repair (MMR) genes and proofreading gene POLE all together were mutated in one third of the ESC patients.
CONCLUSIONS: This is the first study to unravel the mutational profile of ESC tumors. Our findings could match 9 patients to the targeted therapies currently available in clinical practice or in active clinical trials, suggesting the potential utility of targeted therapies for this rare disease in the future.
Roussy M, Bilodeau M, Jouan L, et al.NUP98-BPTF gene fusion identified in primary refractory acute megakaryoblastic leukemia of infancy.
Genes Chromosomes Cancer. 2018; 57(6):311-319 [PubMed
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The advent of large scale genomic sequencing technologies significantly improved the molecular classification of acute megakaryoblastic leukaemia (AMKL). AMKL represents a subset (∼10%) of high fatality pediatric acute myeloid leukemia (AML). Recurrent and mutually exclusive chimeric gene fusions associated with pediatric AMKL are found in 60%-70% of cases and include RBM15-MKL1, CBFA2T3-GLIS2, NUP98-KDM5A and MLL rearrangements. In addition, another 4% of AMKL harbor NUP98 rearrangements (NUP98r), with yet undetermined fusion partners. We report a novel NUP98-BPTF fusion in an infant presenting with primary refractory AMKL. In this NUP98r, the C-terminal chromatin recognition modules of BPTF, a core subunit of the NURF (nucleosome remodeling factor) ATP-dependent chromatin-remodeling complex, are fused to the N-terminal moiety of NUP98, creating an in frame NUP98-BPTF fusion, with structural homology to NUP98-KDM5A. The leukemic blasts expressed two NUP98-BPTF splicing variants, containing one or two tandemly spaced PHD chromatin reader domains. Our study also identified an unreported wild type BPTF splicing variant encoding for 2 PHD domains, detected both in normal cord blood CD34
Dai B, Huang H, Guan F, et al.Histone demethylase KDM5A inhibits glioma cells migration and invasion by down regulating ZEB1.
Biomed Pharmacother. 2018; 99:72-80 [PubMed
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Malignant gliomas are highly lethal cancers worldwide as tumor cells infiltrate to healthy brain tissue invariably. Histone demethylase KDM5A as an oncogene or tumor suppressor in cancer still has been controversial. KDM5A may have a different function in different type cancer cells. However, the specific roles of KDM5A in the progression of glioma remain undiscovered. In this study, we found that compared with primary glioma, metastasis glioma had low KDM5A levels. Besides, lower KDM5A levels were linked to poor survival in glioma cancer patients, indicating that KDM5A is a new prognostic marker for glioma cancer. KDM5A knockdown increases the invasive abilities of glioma cancer cells and changes the EMT markers. A mechanism, KDM5A suppressing the expression of ZEB1, and its catalytic activity is indispensable for anti-invasive function. Our study revealed that histone demethylase KDM5A exerts anti-invasiveness function partly through repressing oncogenic ZEB1 expression by mediating H3K4 demethylation. We also demonstrate that ZEB1 play a crucial role in KDM5A induced function. In summary, in this study, we showed that KDM5A has a crucial role in glioma and therefore may serve as a novel therapeutic target and prognostic marker in glioma.
BACKGROUND: Histone demethylase JARID1B plays several context dependent roles in epigenetic regulation of cellular differentiation in normal development and is highly expressed in multiple human cancers. The protein is a strong transcriptional repressor capable of downregulating numerous genes. There are three splicing isoforms of JARID1B, however the links between the protein structure and function are not clear. The expression pattern of JARID1B in human melanoma seems to be different from observed in other cancers. Moreover, up to now no data on the impact of JARID1B expression in cutaneous melanoma on the patients' prognosis have been reported.
METHODS: We investigated immunohistochemically the association of intratumoral expression of total JARID1B protein and its RBP2-H1 isoform in primary and metastatic melanomas with prognosis for the patients.
RESULTS: Expression of both total JARID1B protein and its RBP2-H1 variant was found in all the melanomas investigated. Our results indicate, however, that only high (above 90% of the cells) intratumoral expression of RBP2-H1 can be considered prognostic factor associated with worse overall survival of the patients.
CONCLUSIONS: Such results if considered together with data demonstrating a switch to enhanced expression of RBP2-H1 at early stages of malignant transformation of melanocytes are in agreement with hypothetical crucial role of JARID1B in the course of melanoma development and progression and suggest that altered splicing of JARID1B may be important factor increasing melanoma aggressiveness.
Choi HJ, Joo HS, Won HY, et al.Role of RBP2-Induced ER and IGF1R-ErbB Signaling in Tamoxifen Resistance in Breast Cancer.
J Natl Cancer Inst. 2018; 110(4) [PubMed
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Background: Despite the benefit of endocrine therapy, acquired resistance during or after treatment still remains a major challenge in estrogen receptor (ER)-positive breast cancer. We investigated the potential role of histone demethylase retinoblastoma-binding protein 2 (RBP2) in endocrine therapy resistance of breast cancer.
Methods: Survival of breast cancer patients according to RBP2 expression was analyzed in three different breast cancer cohorts including METABRIC (n = 1980) and KM plotter (n = 1764). RBP2-mediated tamoxifen resistance was confirmed by invitro sulforhodamine B (SRB) colorimetric, colony-forming assays, and invivo xenograft models (n = 8 per group). RNA-seq analysis and receptor tyrosine kinase assay were performed to identify the tamoxifen resistance mechanism by RBP2. All statistical tests were two-sided.
Results: RBP2 was associated with poor prognosis to tamoxifen therapy in ER-positive breast cancer (P = .04 in HYU cohort, P = .02 in KM plotter, P = .007 in METABRIC, log-rank test). Furthermore, RBP2 expression was elevated in patients with tamoxifen-resistant breast cancer (P = .04, chi-square test). Knockdown of RBP2 conferred tamoxifen sensitivity, whereas overexpression of RBP2 induced tamoxifen resistance invitro and invivo (MCF7 xenograft: tamoxifen-treated control, mean [SD] tumor volume = 70.8 [27.9] mm3, vs tamoxifen-treated RBP2, mean [SD] tumor volume = 387.9 [85.1] mm3, P < .001). Mechanistically, RBP2 cooperated with ER co-activators and corepressors and regulated several tamoxifen resistance-associated genes, including NRIP1, CCND1, and IGFBP4 and IGFBP5. Furthermore, epigenetic silencing of IGFBP4/5 by RBP2-ER-NRIP1-HDAC1 complex led to insulin-like growth factor-1 receptor (IGF1R) activation. RBP2 also increased IGF1R-ErbB crosstalk and subsequent PI3K-AKT activation via demethylase activity-independent ErbB protein stabilization. Combinational treatment with tamoxifen and PI3K inhibitor could overcome RBP2-mediated tamoxifen resistance (RBP2-overexpressing cells: % cell viability [SD], tamoxifen = 89.0 [3.8]%, vs tamoxifen with BKM120 = 41.3 [5.6]%, P < .001).
Conclusions: RBP2 activates ER-IGF1R-ErbB signaling cascade in multiple ways to induce tamoxifen resistance, suggesting that RBP2 is a potential therapeutic target for ER-driven cancer.
BACKGROUND Recently, some studies have found that retinoblastoma-binding protein 2 (RBP2) is involved in the development and progression of many kinds of malignant tumors. This study aimed to explore the expression level of RBP2 in hepatocellular carcinoma (HCC) and its prognostic significance. MATERIAL AND METHODS Immunohistochemical analysis was used to evaluate the RBP2 expression level in 130 HCC patients and adjacent normal tissues. Tumor angiogenesis was marked by CD31 and vascular endothelial growth factor (VEGF) staining. Kaplan-Meier and Cox regression analyses were performed to examine the relationship between RBP2 expression and prognosis of HCC patients. RESULTS RBP2 expression was significantly higher in HCC tissues (positive expression rate: 72.3%, 94/130). Increased RBP2 expression was dramatically associated with AFP level (P=0.016), degree of differentiation (P=0.000), and TNM stage (P=0.035). Moreover, tumors with RBP2-positive expression showed significantly higher intratumoral MVD than those with RBP2-negative expression (P=0.000). Kaplan-Meier analysis revealed RBP2-positive expression was related to decreased disease-free survival (DFS) (P=0.000) and overall survival (OS) (P=0.000). Furthermore, RBP2 was an independent poor prognostic factor of DFS and OS (P=0.029 and 0.010, respectively) as demonstrated by multivariate analysis. CONCLUSIONS Increased RBP2 expression, as an independent poor prognostic factor for DFS and OS of HCC patients, is closely related to tumor angiogenesis. RBP2 is expected to become a new potential therapeutic target for HCC.
Fan L, Hong J, Huang H, et al.High Expression of Phosphorylated Extracellular Signal-Regulated Kinase (ERK1/2) is Associated with Poor Prognosis in Newly Diagnosed Patients with Multiple Myeloma.
Med Sci Monit. 2017; 23:2636-2643 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND Previous research has demonstrated that the extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway is commonly activated in multiple myeloma (MM) patients. However, the prognostic value of activation of the MEK/ERK signaling pathway in newly diagnosed patients with MM has not been reported. MATERIAL AND METHODS Expression levels of p-ERK1/2 protein in bone marrow biopsy specimens obtained from 60 newly diagnosed patients with MM were analyzed using immunohistochemistry, and classified into 3 groups: high p-ERK1/2 expression, low p-ERK1/2 expression, and negative group. Correlations between clinicopathological characteristics, including expression levels of p-ERK1/2 protein, progression-free survival (PFS), and overall survival (OS), were analyzed using univariate and multivariate analysis. RESULTS Phosphorylated-ERK1/2 protein was positive in 47 bone marrow specimens, including 19 specimens with high p-ERK1/2 expression and 28 specimens with low p-ERK1/2 expression. Univariate Kaplan-Meier analysis showed that in newly diagnosed patients with MM, high p-ERK1/2 expression, high ISS staging, serum creatinine (Scr) ≥177 μmol/l, serum β2-microglobulin (β2-MG) ≥5.5 μmol/l, and serum calcium (Ca) ≥2.75 mmol/l were significantly associated with shorter OS and PFS. Additionally, high ECOG scores (score 2-4) were associated with shorter PFS in newly diagnosed patients with MM. Multivariate Cox regression analysis showed that in newly diagnosed patients with MM, high p-ERK1/2 expression was significantly associated with shorter OS and PFS. Additionally, in newly diagnosed patients with MM, serum Ca ≥2.75 mmol/l was significantly associated with shorter PFS, and serum β2-MG ≥5.5 μmol/l was significantly associated with shorter OS. CONCLUSIONS High p-ERK1/2 expression is an independent factor for poor prognosis in newly diagnosed patients with MM.
In glioblastoma several histone demethylase genes (KDM) are overexpressed compared to normal brain tissue and the development of Temozolomide (TMZ) resistance is accompanied by the transient further increased expression of KDM5A and other KDMs following a mechanism that we defined as "epigenetic resilience". We hypothesized that targeting KDMs may kill the cells that survive the cytotoxic therapy.We determined the effect of JIB 04 and CPI-455, two KDM inhibitors, on glioblastoma cells and found that both molecules are more effective against TMZ-resistant rather than native cells.Because of its lower IC50, we focused on JIB 04 that targets KDM5A and other KDMs as well. We have shown that this molecule activates autophagic and apoptotic pathways, interferes with cell cycle progression, inhibits cell clonogenicity and dephosphorylates Akt thus inactivating a potent pro-survival pathway. We performed combination temozolomide/JIB 04 in vitro treatments showing that these two molecules, under certain conditions, have a strong synergic effect and we hypothesize that JIB 04 intercepts the cells that escape the G2 block exerted by TMZ. Finally we studied the permeability of JIB 04 across the blood-brain barrier and found that this molecule reaches bioactive concentration in the brain; furthermore a pilot in vivo experiment in an orthotopic GB xenograft model showed a trend toward longer survival in treated mice with an Hazard Ratio of 0.5.In conclusion we propose that the combination between cytotoxic drugs and molecules acting on the epigenetic landscape may offer the opportunity to develop new therapies for this invariably lethal disease.
Tumber A, Nuzzi A, Hookway ES, et al.Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells.
Cell Chem Biol. 2017; 24(3):371-380 [PubMed
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Methylation of lysine residues on histone tail is a dynamic epigenetic modification that plays a key role in chromatin structure and gene regulation. Members of the KDM5 (also known as JARID1) sub-family are 2-oxoglutarate (2-OG) and Fe
The complexity by which cells regulate gene and protein expression is multifaceted and intricate. Regulation of 3' untranslated region (UTR) processing of mRNA has been shown to play a critical role in development and disease. However, the process by which cells select alternative mRNA forms is not well understood. We discovered that the
Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) in which cells morphologically resemble abnormal megakaryoblasts. While rare in adults, AMKL accounts for 4-15% of newly diagnosed childhood AML cases. AMKL in individuals without Down syndrome (non-DS-AMKL) is frequently associated with poor clinical outcomes. Previous efforts have identified chimeric oncogenes in a substantial number of non-DS-AMKL cases, including RBM15-MKL1, CBFA2T3-GLIS2, KMT2A gene rearrangements, and NUP98-KDM5A. However, the etiology of 30-40% of cases remains unknown. To better understand the genomic landscape of non-DS-AMKL, we performed RNA and exome sequencing on specimens from 99 patients (75 pediatric and 24 adult). We demonstrate that pediatric non-DS-AMKL is a heterogeneous malignancy that can be divided into seven subgroups with varying outcomes. These subgroups are characterized by chimeric oncogenes with cooperating mutations in epigenetic and kinase signaling genes. Overall, these data shed light on the etiology of AMKL and provide useful information for the tailoring of treatment.
Hara Y, Shiba N, Ohki K, et al.Prognostic impact of specific molecular profiles in pediatric acute megakaryoblastic leukemia in non-Down syndrome.
Genes Chromosomes Cancer. 2017; 56(5):394-404 [PubMed
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Pediatric acute megakaryoblastic leukemia in non-Down syndrome (AMKL) is a unique subtype of acute myeloid leukemia (AML). Novel CBFA2T3-GLIS2 and NUP98-KDM5A fusions recurrently found in AMKL were recently reported as poor prognostic factors. However, their detailed clinical and molecular characteristics in patients treated with recent improved therapies remain uncertain. We analyzed molecular features of 44 AMKL patients treated on two recent Japanese AML protocols, the AML99 and AML-05 trials. We identified CBFA2T3-GLIS2, NUP98-KDM5A, RBM15-MKL1, and KMT2A rearrangements in 12 (27%), 4 (9%), 2 (5%), and 3 (7%) patients, respectively. Among 459 other AML patients, NUP98-KDM5A was identified in 3 patients, whereas CBFA2T3-GLIS2 and RBM15-MKL1 were only present in AMKL. GATA1 mutations were found in 5 patients (11%). Four-year overall survival (OS) and event-free survival (EFS) rates of CBFA2T3-GLIS2-positive patients in AMKL were 41.7% and 16.7%, respectively. Three-year cumulative incidence of relapse in CBFA2T3-GLIS2-positive patients was significantly higher than that of CBFA2T3-GLIS2-negative patients (75.0% vs. 35.7%, P = 0.024). In multivariate analyses, CBFA2T3-GLIS2 was an independent poor prognostic factor for OS (HR, 4.34; 95% CI, 1.31-14.38) and EFS (HR, 2.95; 95% CI, 1.20-7.23). Furthermore, seven (54%) of 13 infant AMKL patients were CBFA2T3-GLIS2-positive. Notably, out of 7 CBFA2T3-GLIS2-positive infants, six (86%) relapsed and five (71%) died. Moreover, all of CBFA2T3-GLIS2-positive patients who experienced induction failure (n = 3) were infants, indicating worse prognosis of CBFA2T3-GLIS2-positive infants. These findings indicated the significance of CBFA2T3-GLIS2 as a poor prognostic factor in AMKL patients, particularly in infants.
Post-translational histone H3 modifications regulate transcriptional competence. The mechanisms by which the epigenome is regulated in response to oncogenic signaling remain unclear. Here we show that H3K4me3 is increased in breast tumors driven by an activated PIK3CA allele and that inhibition of PI3K/AKT signaling reduces promoter-associated H3K4me3 in human breast cancer cells. We show that the H3K4 demethylase KDM5A is an AKT target and that phosphorylation of KDM5A regulates its nuclear localization and promoter occupancy. Supporting a role for KDM5A in mediating PI3K/AKT transcriptional effects, the decreased expression in response to AKT inhibition of a subset of cell-cycle genes associated with poor clinical outcome is blunted by KDM5A silencing. Our data identify a mechanism by which PI3K/AKT signaling modulates the cancer epigenome through controlling H3K4 methylation and suggest that KDM5A subcellular localization and genome occupancy may be pharmacodynamic markers of the activity of PI3K/AKT inhibitors currently in clinical development.
Genetic abnormalities and early treatment response are the main prognostic factors in acute myeloid leukemia (AML). Acute megakaryoblastic leukemia (AMKL) is a rare subtype of AML. Deep sequencing has identified CBFA2T3/GLIS2 and NUP98/KDM5A as recurrent aberrations, occurring in similar frequencies as RBM15/MKL1 and KMT2A-rearrangements. We studied whether these cytogenetic aberrations can be used for risk group stratification. To assess frequencies and outcome parameters of recurrent cytogenetic aberrations in AMKL, samples and clinical data of patients treated by the Associazione Italiana Ematologia Oncologia Pediatrica, Berlin-Frankfurt-Munster Study Group, Children's Oncology Group, Dutch Childhood Oncology Group, and the Saint Louis Hôpital were collected, enabling us to screen 153 newly diagnosed pediatric AMKL cases for the aforementioned aberrations and to study their clinical characteristics and outcome. CBFA2T3/GLIS2 was identified in 16% of the cases; RBM15/MKL1, in 12%; NUP98/KDM5A and KMT2A rearrangements, in 9% each; and monosomy 7, in 6%. These aberrations were mutually exclusive. RBM15/MKL1-rearranged patients were significantly younger. No significant differences in sex and white blood cell count were found. NUP98/KDM5A, CBFA2T3/GLIS2, KMT2A-rearranged lesions and monosomy 7 (NCK-7) independently predicted a poor outcome, compared with RBM15/MKL1-rearranged patients and those with AMKL not carrying these molecular lesions. NCK-7-patients (n = 61) showed a 4-year probability of overall survival of 35 ± 6% vs 70 ± 5% in the RBM15/MKL1-other groups (n = 92, P < .0001) and 4-year probability of event-free survival of 33 ± 6% vs 62 ± 5% (P = .0013), the 4-year cumulative incidence of relapse being 42 ± 7% and 19 ± 4% (P = .003), respectively. We conclude that these genetic aberrations may be used for risk group stratification of pediatric AMKL and for treatment tailoring.
Despite recent increases in the cure rate of acute lymphoblastic leukemia (ALL), adult ALL remains a high-risk disease that exhibits a high relapse rate. In this study, we found that the histone demethylase retinoblastoma binding protein-2 (RBP2) was overexpressed in both on-going and relapse cases of adult ALL, which revealed that RBP2 overexpression was not only involved in the pathogenesis of ALL but that its overexpression might also be related to relapse of the disease. RBP2 knockdown induced apoptosis and attenuated leukemic cell viability. Our results demonstrated that BCL2 is a novel target of RBP2 and supported the notion of RBP2 being a regulator of BCL2 expression via directly binding to its promoter. As the role of RBP2 in regulating apoptosis was confirmed, RBP2 overexpression and activation of BCL2 might play important roles in ALL development and progression.
Recent work from others and us revealed interactions between the Sin3/HDAC complex, the H3K4me3 demethylase KDM5A, GATAD1, and EMSY. Here, we characterize the EMSY/KDM5A/SIN3B complex in detail by quantitative interaction proteomics and ChIP-sequencing. We identify a novel substoichiometric interactor of the complex, transcription factor ZNF131, which recruits EMSY to a large number of active, H3K4me3 marked promoters. Interestingly, using an EMSY knock-out line and subsequent rescue experiments, we show that EMSY is in most cases positively correlated with transcriptional activity of its target genes and stimulates cell proliferation. Finally, by immunohistochemical staining of primary breast tissue microarrays we find that EMSY/KDM5A/SIN3B complex subunits are frequently overexpressed in primary breast cancer cases in a correlative manner. Taken together, these data open venues for exploring the possibility that sporadic breast cancer patients with EMSY amplification might benefit from epigenetic combination therapy targeting both the KDM5A demethylase and histone deacetylases.
Notwithstanding current multimodal treatment, including surgery, radiotherapy and chemotherapy with temozolomide (TMZ), median survival of glioblastoma (GBM) patients is about 14 months, due to the rapid emergence of cell clones resistant to treatment. Therefore, understanding the mechanisms underlying chemoresistance is mandatory to improve treatments' outcome. We generated TMZ resistant cells (TMZ-R) from a GBM cell line and from cancer stem cell-enriched cultures isolated from human GBMs. We demonstrated that TMZ resistance is partially reverted by "drug wash-out" suggesting the contribution of epigenetic mechanisms in drug resistance and supporting the possibility of TMZ rechallenge in GBM patients after prior drug exposure. The expression of histone lysine demethylase genes (KDMs) was increased in TMZ-R cells compared to parental cells, and TMZ resistance or restored sensitivity was mimicked by over-expressing or inactivating KDM5A. Methylation and expression of O6-methylguanine-DNA methyltransferase (MGMT) and drug efflux mechanisms were not altered in TMZ-R cells compared to parental TMZ sensitive cells. TMZ-R cells transiently acquired morphologic and molecular characteristics of differentiated tumor cells, features that were lost after drug wash-out. In conclusion, we demonstrated that treatment-induced TMZ resistance in GBM involves epigenetic mechanisms in a subset of slow-cycling and transiently partially differentiated cells that escape drug cytotoxicity, overcome G2 checkpoint and sustain clonal growth. We found that TMZ-R cells are sensitive to histone deacethylase inhibitors (HDACi) that synergize with TMZ. This strong synergism could be exploited to develop novel combined adjuvant therapies for this rapidly progressing and invariably lethal cancer.
Qiao N, Wang S, Hu LRetinoblastoma-binding protein 2 induces epithelial-mesenchymal transition in esophageal squamous cancer cells.
Biotechnol Lett. 2015; 37(12):2365-70 [PubMed
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OBJECTIVES: To investigate the effect of retinoblastoma-binding protein 2 (RBP2) on epithelial-mesenchymal transition (EMT) in esophageal squamous cancer cells and to compare the effect of RBP2 in lung squamous cancer cells and esophageal squamous cancer cells.
RESULTS: When transfected with RBP2 siRNA, the migrated cells were 36.3 ± 6.03 by transwell migration assay, compared to 107 ± 6.7 cells in the control group. The mRNA level of epithelial cadherin (E-cadherin) was 1.54 ± 0.14 times higher than in the control group, and that of neural cadherin (N-cadherin) fell to 0.76 ± 0.03 times. The relative luciferase activity of E-cadherin promoter rose to 3.84 ± 0.23 times. Correspondingly, the expression of E-cadherin protein increased and that of N-cadherin protein decreased. When SK-MES-1 cells were transfected with RBP2 siRNA, their relative mRNA level of E-cadherin was 8.6 ± 0.37 times as high as that in control group, which was higher than that in Eca-109 cells. The E-cadherin protein was also greater in SK-MES-1 cells.
CONCLUSION: RBP2 could induce EMT in esophageal cancer cells and exert a greater effect on the expression of E-cadherin in lung squamous cells than in esophageal squamous cells.
Some feedback pathways are critical in the process of tumor development or malignant progression. However the mechanisms through which these pathways are epigenetically regulated have not been fully elucidated. Here, we demonstrated that the histone demethylase RBP2 was crucial for TGF-β1-(p-Smad3)-RBP2-E-cadherin-Smad3 feedback circuit that was implicated in malignant progression of tumors and its knockdown significantly inhibited gastric cancer (GC) metastasis both in vitro and in vivo. Mechanistically, RBP2 can directly bind to E-cadherin promoter and suppress its expression, facilitating EMT and distant metastasis of GC. RBP2 can also be induced by TGF-β1, a key inducer of EMT, through phosphorylated Smad3 (p-Smad3) pathway in GC. The upregulated RBP2 can be recruited by p-smad3 to E-cadherin promoter and enhance its suppression, contributing to the promotion of metastasis of GC. In addition, the suppression of E-cadherin by RBP2 attenuated inhibition of Smad3 phosphorylation (exerted by E-cadherin), resulting further induction of RBP2 expression, and thus constituting positive feedback regulation during GC malignant progression. This TGF-β1-(p-Smad3)-RBP2-E-cadherin-Smad3 feedback circuit may be a novel mechanism for GC malignant progression and suppression of RBP2 expression may serve as a new strategy for the prevention of tumor distant metastasis.
Clear cell renal cell carcinoma (ccRCC) is the major subtype of kidney cancer that is characterized by frequent inactivation of the von Hippel-Lindau (VHL) gene in 80-90% of the tumors. Recent reports using massive parallel sequencing technologies have discovered additional cancer driver genes. PBRM1 was found to be mutated in about 40% of ccRCC tumors, whereas BAP1 and SETD2 were each mutated in about 10-15% of ccRCC tumors. JARID1C and UTX, two histone H3 demethylases, were also found to harbor mutations in ccRCC, albeit at lower rates. ccRCC tumors display a high degree of intra-tumoral heterogeneity, with some mutations present in all cancer cells (ubiquitous), whereas others are subclonal. The VHL mutations were always ubiquitous in the tumors; PBRM1 mutations were also ubiquitous but to a lesser extent. On the contrary, mutations in BAP1, SETD2, JARID1C, and UTX were all subclonal, meaning that they were present in a subset of cancer cells in a tumor. The prognostic value of PBRM1 mutations in ccRCC is still controversial, whereas BAP1 mutations were tightly linked to worse clinical outcomes in multiple studies. The molecular functions of these newly identified cancer driver genes are discussed, and they were known readers, writers, or erasers of histone marks on histone H2 and H3 tails that are very close to each other, suggesting that these factors might functionally interact and affect common pathways. The studies on these newly identified tumor suppressors will shed light on ccRCC tumorigenesis and development, and will likely lead to development of novel therapeutic interventions for ccRCC patients.
Chronic myeloid leukemia in the blastic phase (CML-BP) responds poorly to clinical treatments and is usually fatal. In this study, we found that the histone H3 lysine 4 (H3K4) demethylase RBP2 (also called JARID1A and KDM5A) is underexpressed in CML-BP. The RBP2 histone demethylase stimulates leukemia cell differentiation and inhibits cell proliferation. We identified miR-21 was directly downregulated by RBP2 and found that miR-21 downregulated PDCD4 expression in leukemia cells. By binding to miR-21 promoter and by demethylating of trimethylated H3K4 at the miR-21 locus, RBP2 downregulated miR-21 expression. This in turn activated PDCD4. In conclusion, RBP2 epigenetically downregulated miR-21 in blast transformation of CML.
Lin W, Watanabe H, Peng S, et al.Dynamic epigenetic regulation by menin during pancreatic islet tumor formation.
Mol Cancer Res. 2015; 13(4):689-98 [PubMed
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UNLABELLED: The tumor suppressor gene MEN1 is frequently mutated in sporadic pancreatic neuroendocrine tumors (PanNET) and is responsible for the familial multiple endocrine neoplasia type 1 (MEN-1) cancer syndrome. Menin, the protein product of MEN1, associates with the histone methyltransferases (HMT) MLL1 (KMT2A) and MLL4 (KMT2B) to form menin-HMT complexes in both human and mouse model systems. To elucidate the role of methylation of histone H3 at lysine 4 (H3K4) mediated by menin-HMT complexes during PanNET formation, genome-wide histone H3 lysine 4 trimethylation (H3K4me3) signals were mapped in pancreatic islets using unbiased chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq). Integrative analysis of gene expression profiles and histone H3K4me3 levels identified a number of transcripts and target genes dependent on menin. In the absence of Men1, histone H3K27me3 levels are enriched, with a concomitant decrease in H3K4me3 within the promoters of these target genes. In particular, expression of the insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) gene is subject to dynamic epigenetic regulation by Men1-dependent histone modification in a time-dependent manner. Decreased expression of IGF2BP2 in Men1-deficient hyperplastic pancreatic islets is partially reversed by ablation of RBP2 (KDM5A), a histone H3K4-specific demethylase of the jumonji, AT-rich interactive domain 1 (JARID1) family. Taken together, these data demonstrate that loss of Men1 in pancreatic islet cells alters the epigenetic landscape of its target genes.
IMPLICATIONS: Epigenetic profiling and gene expression analysis in Men1-deficient pancreatic islet cells reveals vital insight into the molecular events that occur during the progression of pancreatic islet tumorigenesis.
BACKGROUND: Pathological angiogenesis plays an essential role in tumor aggressiveness and leads to unfavorable prognosis. The aim of this study is to detect the potential role of Retinoblastoma binding protein 2 (RBP2) in the tumor angiogenesis of non-small cell lung cancer (NSCLC).
METHODS: Immunohistochemical staining was used to detect the expression of RBP2, hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and CD34. Two pairs of siRNA sequences and pcDNA3-HA-RBP2 were used to down-regulate and up-regulate RBP2 expression in H1975 and SK-MES-1 cells. An endothelial cell tube formation assay, VEGF enzyme-linked immunosorbent assay, real-time PCR and western blotting were performed to detect the potential mechanisms mediated by RBP2 in tumor angiogenesis.
RESULTS: Of the 102 stage I NSCLC specimens analyzed, high RBP2 protein expression is closely associated with tumor size (P = 0.030), high HIF-1α expression (P = 0.028), high VEGF expression (P = 0.048), increased tumor angiogenesis (P = 0.033) and poor prognosis (P = 0.037); high MVD was associated with high HIF-1α expression (P = 0.034), high VEGF expression (P = 0.001) and poor prognosis (P = 0.040). Multivariate analysis indicated that RBP2 had an independent influence on the survival of patients with stage I NSCLC (P = 0.044). By modulating the expression of RBP2, our findings suggested that RBP2 protein depletion decreased HUVECs tube formation by down-regulating VEGF in a conditioned medium. RBP2 stimulated the up-regulation of VEGF, which was dependent on HIF-1α, and activated the HIF-1α via phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Moreover, VEGF increased the activation of Akt regulated by RBP2.
CONCLUSIONS: The RBP2 protein may stimulate HIF-1α expression via the activation of the PI3K/Akt signaling pathway under normoxia and then stimulate VEGF expression. These findings indicate that RBP2 may play a critical role in tumor angiogenesis and serve as an attractive therapeutic target against tumor aggressiveness for early-stage NSCLC patients.
Rasmussen PB, Staller PThe KDM5 family of histone demethylases as targets in oncology drug discovery.
Epigenomics. 2014; 6(3):277-86 [PubMed
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There is growing evidence for a causal role of the KDM5 family of histone demethylases in human cancer. In particular, KDM5A (JARID1A/RBP2) and KDM5B (JARID1B/PLU1) contribute to cancer cell proliferation, reduce the expression of tumor suppressor genes, promote the development of drug tolerance and maintain tumor-initiating cells. KDM5 enzymes remove tri- and di-methylations of lysine 4 of histone H3 - modifications that occur at the start site of transcription in actively transcribed genes. However, the importance of the histone demethylase activity of KDM5 proteins for cancer cells has not been resolved so far. The currently available approaches suppress or remove the targeted proteins and thereby affect their putative functions as structural components and recruitment factors for other chromatin-associated proteins. Therefore, the development of specific enzymatic inhibitors for KDM5 will promote our understanding of the biological role of their catalytic activity and yield potential novel anticancer therapeutics.
BACKGROUND: The molecular mechanisms responsible for angiogenesis and abnormal expression of angiogenic factors in gastric cancer, including vascular endothelial growth factor (VEGF), remain unclear. The histone demethylase retinoblastoma binding protein 2 (RBP2) is involved in gastric tumorgenesis by inhibiting the expression of cyclin-dependent kinase inhibitors (CDKIs).
METHODS: The expression of RBP2, VEGF, CD31, CD34 and Ki67 was assessed in 30 human gastric cancer samples and normal control samples. We used quantitative RT-PCR, western blot analysis, ELISA, tube-formation assay and colony-formation assay to characterize the change in VEGF expression and associated biological activities induced by RBP2 silencing or overexpression. Luciferase assay and ChIP were used to explore the direct regulation of RBP2 on the promoter activity of VEGF. Nude mice and RBP2-targeted mutant mice were used to detect the role of RBP2 in VEGF expression and angiogenesis in vivo.
RESULTS: RBP2 and VEGF were both overexpressed in human gastric cancer tissue, with greater microvessel density (MVD) and cell proliferation as compared with normal tissue. In gastric epithelial cell lines, RBP2 overexpression significantly promoted the expression of VEGF and the growth and angiogenesis of the cells, while RBP2 knockdown had the reverse effect. RBP2 directly bound to the promoter of VEGF to regulate its expression by histone H3K4 demethylation. The subcutis of nude mice transfected with BGC-823 cells with RBP2 knockdown showed reduced VEGF expression and MVD, with reduced carcinogenesis and cell proliferation. In addition, the gastric epithelia of RBP2 mutant mice with increased H3K4 trimethylation showed reduced VEGF expression and MVD.
CONCLUSIONS: The promotion of gastric tumorigenesis by RBP2 was significantly associated with transactivation of VEGF expression and elevated angiogenesis. Overexpression of RBP2 and activation of VEGF might play important roles in human gastric cancer development and progression.
Ramakrishnan SK, Varshney A, Sharma A, et al.Expression of targeted ribozyme against telomerase RNA causes altered expression of several other genes in tumor cells.
Tumour Biol. 2014; 35(6):5539-50 [PubMed
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Telomeres are tandem repeat sequences present at chromosome end that are synthesized by RNA-protein enzyme called telomerase. The RNA component (TR) serves as template for telomerase reverse transcriptase (TERT) for generating telomere repeats. TERT is overexpressed in actively dividing cells including cancerous cells, absent in differentiated somatic cells whereas human telomerase RNA (hTR) is present in normal as well as in cancer cells. Telomerase overexpression in cancer cells ensures telomere length maintenance that actually provides proliferative advantage to cells. Stable expression of ribozyme against hTR in HeLa cells results in reduction of hTR levels, telomerase activity, and telomere length which is accompanied by altered cell morphology and expression of several specific cellular genes. The altered genes deduced from differentially display PCR and 2D gel electrophoresis upon hTR knockdown have function in ribosome biogenesis, chromatin modulation, cell cycle control, and p63-dependant pathways. Our observations shows hTR participates in diverse cellular functions other than telomere maintenance, validates as a possible drug targets in p53- and pRB-negative status, and indicated possible cross-talks between telomerase and other cellular pathways.