The Inhibition of the Histone Methyltransferase EZH2 by DZNEP or SiRNA Demonstrates Its Involvement in MGMT, TRA2A, RPS6KA2, and U2AF1 Gene Regulation in Prostate Cancer

Ouardi, Driss El; Idrissou, Mouhamed; Sánchez, Alcides Antúnez; Penault‐Llorca, Frédérique; Bignon, Yves‐Jean; Guy, Laurent; Bernard‐Gallon, Dominique

doi:10.1089/omi.2019.0162

Cited by 7 publications

(4 citation statements)

References 7 publications

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“…Our results support the oncosuppressive role of HNF1B in prostate carcinoma, which may be silenced due to promoter methylation and other mechanisms, but not due to gene mutation, which seems to be very rare in PC. Despite the equivocal relations between HNF1B, EZH2 and ECI2, the high expression of EZH2 and ECI2 in PC seems to be a potential therapeutic target, especially in the case of EZH2 as suggested in previous studies 17,[58][59][60][61][62][63] .…”

Section: Scientific Reports |mentioning

confidence: 99%

HNF1B, EZH2 and ECI2 in prostate carcinoma. Molecular, immunohistochemical and clinico-pathological study

Dundr

Bártů

Hojný

et al. 2020

Sci Rep

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Hepatocyte nuclear factor 1 beta (HNF1B) is a tissue specific transcription factor, which seems to play an important role in the carcinogenesis of several tumors. In our study we focused on analyzing HNF1B in prostate carcinoma (PC) and adenomyomatous hyperplasia (AH), as well as its possible relation to the upstream gene EZH2 and downstream gene ECI2. The results of our study showed that on an immunohistochemical level, the expression of HNF1B was low in PC, did not differ between PC and AH, and did not correlate with any clinical outcomes. In PC, mutations of HNF1B gene were rare, but the methylation of its promotor was a common finding and was positively correlated with Gleason score and stage. The relationship between HNF1B and EZH2/ECI2 was equivocal, but EZH2 and ECI2 were positively correlated on both mRNA and protein level. The expression of EZH2 was associated with poor prognosis. ECI2 did not correlate with any clinical outcomes. Our results support the oncosuppressive role of HNF1B in PC, which may be silenced by promotor methylation and other mechanisms, but not by gene mutation. The high expression of EZH2 (especially) and ECI2 in PC seems to be a potential therapeutic target. Hepatocyte nuclear factor 1 beta (HNF1B) is an important tissue specific transcription factor, which is essential for the embryonic development of several organs including the kidney, pancreas, liver, biliary tract, genital tract, and gastrointestinal system 1,2. Heterozygous germline mutations are associated with several congenital diseases of the kidney, pancreas, and urogenital tract, and the role of HNF1B in these diseases is well known 3-5. However, despite the increased awareness that HNF1B plays an important role in the carcinogenesis of several solid tumors, the exact significance of HNF1B in carcinogenesis is not yet fully understood 6-9. The regulatory mechanisms and pathways in which HNF1B is involved in the process of carcinogenesis are not clear, but it appears that HNF1B may act as either oncogene or oncosuppressor gene based on the type of tumor and its histogenesis 6,7,10. In the prostate, an increased expression of HNF1B seems to be protective against prostate cancer, and HNF1B therefore has been attributed an oncosuppressive role 10. However, the levels of protein expression of HNF1B in prostate cancer are not well known, and the mechanisms playing role in its regulation are of interest. According to current knowledge, HNF1B is commonly inactivated in prostate cancer, especially due to HNF1B promoter methylation, which occurs in about 50% of cases 11. Another recently suggested possible mechanisms of HNF1B inactivation is the effect of the enhancer of zeste homolog 2 (EZH2), the overexpression of which has been suggested to downregulate the expression of HNF1B 12,13. EZH2 is a gene belonging to the category of Polycomb

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Section: Scientific Reports |mentioning

confidence: 99%

HNF1B, EZH2 and ECI2 in prostate carcinoma. Molecular, immunohistochemical and clinico-pathological study

Dundr

Bártů

Hojný

et al. 2020

Sci Rep

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“…The functions of RPS6K family has been proposed, which include phosphorylation of c-Fos, oestrogen receptor, nuclear factor-kappa B/IkBa, CREB, histones, Myt1, glycogen synthase kinase-3, BAD and regulation of gene expression ( 34 ). RPS6KA2 was first isolated in 1994 and encoded a protein of approximately 90 kDa that acts downstream of MAP kinases to transduce a variety of signals from the cell surface induced by growth factors or stress to the nucleus ( 35 , 36 ).RPS6KA2 has been confirmed to play an important role in prostate cancer, pancreatic cancer, colon or rectal cancer ( 37 – 39 ). In our study, we found RPS6KA2 was related to the prognosis of ovarian cancer through TCGA, GSE26712 and GSE26193, the highly expression of RPS6KA2 had a better prognosis in ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

ncRNAs mediated RPS6KA2 inhibits ovarian cancer proliferation via p38/MAPK signaling pathway

Ding

Gong

et al. 2023

Front. Oncol.

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BackgroundOvarian cancer is the most lethal gynecology malignancy in the world, therefore, research on the molecular biological mechanism of ovarian cancer tumorigenesis and progression has received widespread attention.MethodsWe identified RPS6KA2 as the prognosis-related gene of ovarian cancer from TCGA, GSE26712 and GSE26193 database via bioinformatic analysis. qRT-PCR and western blot detected the differential expression of RPS6KA2 in normal ovaries and ovarian cancer tissues. The biological functions of RPS6KA2 were verified by in vitro and in vivo. GSEA analysis was used to select candidate signaling pathway of RPS6KA2 which was further verified by western blot. The possible binding sites of RPS6KA2 with miRNAs and circRNAs were predicted by bioinformatics analysis, and then a circRNA-miRNA-mRNA interaction network was constructed.ResultsWe found the expression of RPS6KA2 was down-regulated in ovarian cancer tissues. Overexpression of RPS6KA2 could suppress cell proliferation, whereas knockdown of RPS6KA2 had the opposite effects on proliferation. GSEA analysis showed that the MARK signaling pathway was closely associated with RPS6KA2. Bioinformatics analysis and dual-luciferase reporter assay showed that RPS6KA2 was regulated with miR-19a-3p, miR-106a-5p and miR-519d-3p. Further analysis showed that circFAM169A was the common ceRNA of miR-19a-3p, miR-106a-5p and miR-519d-3p. Dual-luciferase reporter assay showed the relationship of circFAM169A and miR-106a-5p and miR-519d-3p. After network analysis, one circRNA-miRNA-mRNA axis (circFAM169A/miR-106a-5p, miR-519d-3p/RPS6KA2) was identified.ConclusionsWe demonstrated that circFAM169A/miR-106a-5p, miR-519d-3p mediated low expression of RPS6KA2 could affect the proliferation of ovarian cancer cells via p38/MAPK signaling pathway.

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“…In summary, downregulation of U2AF1 can cause androgen resistance and increased proliferation of prostate cancer cells through the regulation of ARV7 splicing and an increase in MAPK1 expression, predicting a poor prognosis in patients with this cancer ( 82 ). A further study based on prostate tumour biopsies suggested, however, the overexpression of U2AF1 genes in association with EZH2 localized in mRNA and MAPK pathways ( 83 ).…”

Section: U2af1 Mutation In Different Solid Tumoursmentioning

confidence: 99%

U2AF1 in various neoplastic diseases and relevant targeted therapies for malignant cancers with complex mutations (Review)

Nian,

Li,

et al. 2023

Oncol Rep

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U2 small nuclear RNA auxiliary factor 1 (U2AF1) is a multifunctional protein that plays a crucial role in the regulation of RNA splicing during eukaryotic gene expression. U2AF1 belongs to the SR family of splicing factors and is involved in the removal of introns from mRNAs and exon-exon binding. Mutations in U2AF1 are frequently observed in myelodysplastic syndrome, primary myelofibrosis, chronic myelomonocytic leukaemia, hairy cell leukaemia and other solid tumours, particularly in lung, pancreatic, and ovarian carcinomas. Therefore, targeting U2AF1 for therapeutic interventions may be a viable strategy for treating malignant diseases. In the present review, the pathogenic mechanisms associated with U2AF1 in different malignant diseases were summarized, and the potential of related targeting agents was discussed. Additionally, the feasibility of natural product-based therapies directed against U2AF1 was explored.

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The Inhibition of the Histone Methyltransferase EZH2 by DZNEP or SiRNA Demonstrates Its Involvement in MGMT, TRA2A, RPS6KA2, and U2AF1 Gene Regulation in Prostate Cancer

Cited by 7 publications

References 7 publications

HNF1B, EZH2 and ECI2 in prostate carcinoma. Molecular, immunohistochemical and clinico-pathological study

HNF1B, EZH2 and ECI2 in prostate carcinoma. Molecular, immunohistochemical and clinico-pathological study

ncRNAs mediated RPS6KA2 inhibits ovarian cancer proliferation via p38/MAPK signaling pathway

U2AF1 in various neoplastic diseases and relevant targeted therapies for malignant cancers with complex mutations (Review)

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