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MEF2?activated long non?coding RNA PCGEM1 promotes cell proliferation in hormone?refractory prostate cancer through downregulation of miR?148a.

ABSTRACT: Prostate cancer gene expression marker 1 (PCGEM1) is a prostate?specific gene overexpressed in prostate cancer cells that promotes cell proliferation. To study the molecular mechanism of PCGEM1 function in hormone?refractory prostate cancer, the interaction between myocyte enhancer factor 2 (MEF2) and PCGEM1 was assessed by a luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay. In addition, the underlying mechanism of PCGEM1 regulating expression of microRNA (miR)?148a in PC3 prostate cancer cells was evaluated. Relative expression levels were measured by reverse transcription?quantitative polymerase chain reaction, and early apoptosis was measured by flow cytometry. PCGEM1 was demonstrated to be overexpressed in prostate cancer tissues compared with noncancerous tissues. Expression levels of PCGEM1 in PC3 cancer cells were demonstrated to be regulated by MEF2, as PCGME1 mRNA was increased by MEF2 overexpression but decreased by MEF2 silencing. MEF2 was also demonstrated to enhance the activity of PCGEM1 promoter and thus promote PCGEM1 transcription. In addition, downregulation of PCGEM1 expression in PC3 cells increased expression of miR?148a. By contrast, overexpression of PCGEM1 decreased miR?148a expression. Finally, PCGME1 silencing by small interfering RNA significantly induced early cell apoptosis but this effect was reduced by a miR?148a inhibitor. In conclusion, the present study demonstrated a positive regulatory association between MEF2 and PCGEM1, and a reciprocal negative regulatory association between PCGEM1 and miR?148a that controls cell apoptosis. The present study, therefore, provides new insights into the mechanism of PCGEM1 function in prostate cancer development.

SUBMITTER: Zhang S

PROVIDER: S-EPMC6059670 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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MEF2‑activated long non‑coding RNA PCGEM1 promotes cell proliferation in hormone‑refractory prostate cancer through downregulation of miR‑148a.

Zhang Shibao S Li Zongwu Z Zhang Longyang L Xu Zhonghua Z

Molecular medicine reports 20180504 1

Prostate cancer gene expression marker 1 (PCGEM1) is a prostate‑specific gene overexpressed in prostate cancer cells that promotes cell proliferation. To study the molecular mechanism of PCGEM1 function in hormone‑refractory prostate cancer, the interaction between myocyte enhancer factor 2 (MEF2) and PCGEM1 was assessed by a luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay. In addition, the underlying mechanism of PCGEM1 regulating expression of microRNA (miR)‑148a in PC ...[more]

PMID: 29749452

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Project description:Background:Cervical cancer (CC) is the fourth leading cause of cancer-associated death in women worldwide. Recently, long noncoding RNA (lncRNA) prostate cancer gene expression marker 1 (PCGEM1) has been demonstrated to involve in the initiation and progression of human cancers. However, to date, the clinical and functional significance of PCGEM1 expression in CC progression remains unknown. Methods:qRT-PCR was performed to investigate PCGEM1 expression levels in CC tissues and cell lines. The effect of PCGEM1 on CC cells was assessed by gain- and loss-of-function assays. MS2-binding sequences-MS2-binding protein-based RIP assay (MS2-RIP), RNA pull-down and Luciferase reporter assays were performed to investigate the interaction between PCGEM1 and miR-182. The association between miR-182 and F-box and WD repeat domain containing 11 (FBXW11) was verified by luciferase reporter assay. The effect of PCGEM1 on the NF-?B and ?-catenin/TCF signaling pathways was determined by luciferase reporter assay. Results:Our present study showed that PCGEM1 was significantly upregulated in CC tissues and cell lines. Overexpression of PCGEM1 was correlated with advanced International Federation of Gynecology and Obstetrics (FIGO) stage, lymph node, distant metastasis and poor prognosis in CC patients. Functionally, PCGEM1 promoted cell proliferation, cell cycle progression, migration and invasion, while suppressed cell apoptosis in CC cells. Further mechanistic investigation revealed that PCGEM1 associated with miR-182 and suppressed its expression. PCGEM1 could act as a competing endogenous (ceRNA) of oncogene F-box and WD repeat domain containing 11 (FBXW11) for miR-182 in CC cells. Additionally, PCGEM1 was capable to activate the NF-?B and ?-catenin/TCF signaling pathways, which was reversed by inhibition of FBXW11. Conclusion:In conclusion, our findings demonstrated that PCGEM1-miR-182-FBXW11 axis play an important role in CC progression, and indicated a promising therapeutic target for CC patients.

Project description:BackgroundBreast cancer has one of highest morbidity and mortality rates for women. Abnormalities regarding epigenetics modification and pyruvate dehydrogenase kinase 1 (PDK1)-induced unusual metabolism contribute to breast cancer progression and chemotherapy resistance. However, the role and mechanism of epigenetic change in regulating PDK1 in breast cancer remains to be elucidated.MethodsGene set enrichment analysis (GSEA) and Pearson's correlation analysis were performed to analyze the relationship between histone deacetylase 2 (HDAC2), enhancer of zeste homologue 2 (EZH2), and PDK1 in database and human breast cancer tissues. Dual luciferase reporters were used to test the regulation between PDK1 and miR-148a. HDAC2 and EZH2 were found to regulate miR-148a expression through Western blotting assays, qRT-PCR and co-immunoprecipitation assays. The effects of PDK1 and miR-148a in breast cancer were investigated by immunofluorescence (IF) assay, Transwell assay and flow cytometry assay. The roles of miR-148a/PDK1 in tumor growth were investigated in vivo.ResultsWe found that PDK1 expression was upregulated by epigenetic alterations mediated by HDAC2 and EZH2. At the post-transcriptional level, PDK1 was a new direct target of miR-148a and was upregulated in breast cancer cells due to miR-148a suppression. PDK1 overexpression partly reversed the biological function of miR-148a-including miR-148a's ability to increase cell sensitivity to Adriamycin (ADR) treatment-inhibiting cell glycolysis, invasion and epithelial-mesenchymal transition (EMT), and inducing apoptosis and repressing tumor growth. Furthermore, we identified a novel mechanism: DNMT1 directly bound to EZH2 and recruited EZH2 and HDAC2 complexes to the promoter region of miR-148a, leading to miR-148a downregulation. In breast cancer tissues, HDAC2 and EZH2 protein expression levels also were inversely correlated with levels of miR-148a expression.ConclusionOur study found a new regulatory mechanism in which EZH2 and HDAC2 mediate PDK1 upregulation by silencing miR-148a expression to regulate cancer development and Adriamycin resistance. These new findings suggest that the HDAC2/EZH2/miR-148a/PDK1 axis is a novel mechanism for regulating cancer development and is a potentially promising target for therapeutic options in the future.

Dataset Information

MEF2?activated long non?coding RNA PCGEM1 promotes cell proliferation in hormone?refractory prostate cancer through downregulation of miR?148a.

Publications

MEF2‑activated long non‑coding RNA PCGEM1 promotes cell proliferation in hormone‑refractory prostate cancer through downregulation of miR‑148a.

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