Methylation‐associated miR‐193b silencing activates master drivers of aggressive prostate cancer

Epigenetic silencing of miRNA is a primary mechanism of aberrant miRNA expression in cancer, and hypermethylation of miRNA promoters has been reported to contribute to prostate cancer initiation and progression. Recent data have shown that the miR‐193b promoter is hypermethylated in prostate cancer compared with normal tissue, but studies assessing its functional significance have not been performed. We aimed to elucidate the function of miR‐193b and identify its critical targets in prostate cancer. We observed an inverse correlation between miR‐193b level and methylation of its promoter in The Cancer Genome Atlas (TCGA) cohort. Overexpression of miR‐193b in prostate cancer cell lines inhibited invasion and induced apoptosis. We found that a majority of the top 150 genes downregulated when miR‐193b was overexpressed in liposarcoma are overexpressed in metastatic prostate cancer and that 41 miR‐193b target genes overlapped with the 86 genes in the aggressive prostate cancer subtype 1 (PCS1) signature. Overexpression of miR‐193b led to the inhibition of the majority of the 41 genes in prostate cancer cell lines. High expression of the 41 genes was correlated with recurrence of prostate cancer. Knockdown of miR‐193b targets FOXM1 and RRM2 in prostate cancer cells phenocopied overexpression of miR‐193b. Dual treatment with DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors decreased miR‐193b promoter methylation and restored inhibition of FOXM1 and RRM2. Our data suggest that silencing of miR‐193b through promoter methylation may release the inhibition of PCS1 genes, contributing to prostate cancer progression and suggesting a possible therapeutic strategy for aggressive prostate cancer.

[1]  Henry W. Long,et al.  A Novel Mechanism Driving Poor-Prognosis Prostate Cancer: Overexpression of the DNA Repair Gene, Ribonucleotide Reductase Small Subunit M2 (RRM2) , 2019, Clinical Cancer Research.

[2]  V. Constâncio,et al.  Comparing diagnostic and prognostic performance of two-gene promoter methylation panels in tissue biopsies and urines of prostate cancer patients , 2018, Clinical Epigenetics.

[3]  Á. Aytés,et al.  Epigenetic Regulation in Prostate Cancer Progression , 2018, Current Molecular Biology Reports.

[4]  D. Barros-Silva,et al.  MicroRNA-27a-5p regulation by promoter methylation and MYC signaling in prostate carcinogenesis , 2018, Cell Death & Disease.

[5]  Chunjiao Song,et al.  The potential of microRNAs as human prostate cancer biomarkers: A meta‐analysis of related studies , 2017, Journal of cellular biochemistry.

[6]  Menggang Yu,et al.  Associations of Luminal and Basal Subtyping of Prostate Cancer With Prognosis and Response to Androgen Deprivation Therapy , 2017, JAMA oncology.

[7]  N. Socci,et al.  miR-193b-Regulated Signaling Networks Serve as Tumor Suppressors in Liposarcoma and Promote Adipogenesis in Adipose-Derived Stem Cells. , 2017, Cancer research.

[8]  Xiaoqi Liu,et al.  MicroRNAs in prostate cancer: Functional role as biomarkers. , 2017, Cancer letters.

[9]  A. De Siervi,et al.  Implications of microRNA dysregulation in the development of prostate cancer. , 2017, Reproduction.

[10]  A. Zoubeidi,et al.  Targeting Prostate Cancer Subtype 1 by Forkhead Box M1 Pathway Inhibition , 2017, Clinical Cancer Research.

[11]  Zendra Zehner,et al.  A Panel of MicroRNAs as Diagnostic Biomarkers for the Identification of Prostate Cancer , 2017, International journal of molecular sciences.

[12]  Gerardo Botti,et al.  Micrornas in prostate cancer: an overview , 2017, Oncotarget.

[13]  M. Esteller,et al.  Downregulation of miR-130b~301b cluster is mediated by aberrant promoter methylation and impairs cellular senescence in prostate cancer , 2017, Journal of Hematology & Oncology.

[14]  M. Esteller,et al.  MiR-193b promoter methylation accurately detects prostate cancer in urine sediments and miR-34b/c or miR-129-2 promoter methylation define subsets of clinically aggressive tumors , 2017, Molecular Cancer.

[15]  E. Klein,et al.  Integrated Classification of Prostate Cancer Reveals a Novel Luminal Subtype with Poor Outcome. , 2016, Cancer research.

[16]  C. Walsh,et al.  Regulation of miR‐200c and miR‐141 by Methylation in Prostate Cancer , 2016, The Prostate.

[17]  B. Illades-Aguiar,et al.  Methylation and expression of miRNAs in precancerous lesions and cervical cancer with HPV16 infection. , 2016, Oncology reports.

[18]  E. Lam,et al.  Insights into a Critical Role of the FOXO3a-FOXM1 Axis in DNA Damage Response and Genotoxic Drug Resistance , 2016, Current drug targets.

[19]  Steven J. M. Jones,et al.  The Molecular Taxonomy of Primary Prostate Cancer , 2015, Cell.

[20]  W. Han,et al.  Decitabine, a new star in epigenetic therapy: the clinical application and biological mechanism in solid tumors. , 2014, Cancer letters.

[21]  S. Clark,et al.  Prostate cancer epigenetic biomarkers: next-generation technologies , 2014, Oncogene.

[22]  Mariano J. Alvarez,et al.  Cross-species regulatory network analysis identifies a synergistic interaction between FOXM1 and CENPF that drives prostate cancer malignancy. , 2014, Cancer cell.

[23]  Benjamin E. Gross,et al.  Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal , 2013, Science Signaling.

[24]  B. Bernstein,et al.  Epigenetic Reprogramming in Cancer , 2013, Science.

[25]  Hiromu Suzuki,et al.  DNA methylation and microRNA dysregulation in cancer , 2012, Molecular oncology.

[26]  J. Ji,et al.  Characterization of human gastric carcinoma-related methylation of 9 miR CpG islands and repression of their expressions in vitro and in vivo , 2012, BMC Cancer.

[27]  M. Pagano,et al.  Cyclin F-Mediated Degradation of Ribonucleotide Reductase M2 Controls Genome Integrity and DNA Repair , 2012, Cell.

[28]  Benjamin J. Raphael,et al.  The Mutational Landscape of Lethal Castrate Resistant Prostate Cancer , 2012, Nature.

[29]  G. Stein,et al.  A program of microRNAs controls osteogenic lineage progression by targeting transcription factor Runx2 , 2011, Proceedings of the National Academy of Sciences.

[30]  H. Oja,et al.  miR‐193b is an epigenetically regulated putative tumor suppressor in prostate cancer , 2010, International journal of cancer.

[31]  W. Filipowicz,et al.  The widespread regulation of microRNA biogenesis, function and decay , 2010, Nature Reviews Genetics.

[32]  G. Kristiansen,et al.  Diagnostic and prognostic implications of microRNA profiling in prostate carcinoma , 2009, International journal of cancer.

[33]  A. D. De Marzo,et al.  Epigenetic alterations in human prostate cancers. , 2009, Endocrinology.

[34]  Jing Chen,et al.  ToppGene Suite for gene list enrichment analysis and candidate gene prioritization , 2009, Nucleic Acids Res..

[35]  H. Cedar,et al.  Linking DNA methylation and histone modification: patterns and paradigms , 2009, Nature Reviews Genetics.

[36]  Myles Brown,et al.  The role of microRNA-221 and microRNA-222 in androgen-independent prostate cancer cell lines. , 2009, Cancer research.

[37]  A. Scarpa,et al.  Synergistic effect of trichostatin A and 5‐aza‐2′‐deoxycytidine on growth inhibition of pancreatic endocrine tumour cell lines: A proteomic study , 2009, Proteomics.

[38]  T. Golub,et al.  Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer. , 2008, Journal of the National Cancer Institute.

[39]  C. Creighton,et al.  Widespread deregulation of microRNA expression in human prostate cancer , 2008, Oncogene.

[40]  R. Rees,et al.  DNA demethylation and histone deacetylation inhibition co‐operate to re‐express estrogen receptor beta and induce apoptosis in prostate cancer cell‐lines , 2008, The Prostate.

[41]  F. Lyko,et al.  Methylation of Human MicroRNA Genes in Normal and Neoplastic Cells , 2007, Cell cycle.

[42]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[43]  M. Carducci,et al.  Pharmacokinetics of 5-azacitidine administered with phenylbutyrate in patients with refractory solid tumors or hematologic malignancies. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[44]  M. Becich,et al.  Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[45]  R. Tibshirani,et al.  Gene expression profiling identifies clinically relevant subtypes of prostate cancer. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[46]  M. Grever,et al.  Depsipeptide (FR 901228) promotes histone acetylation, gene transcription, apoptosis and its activity is enhanced by DNA methyltransferase inhibitors in AML1/ETO-positive leukemic cells , 2003, Leukemia.

[47]  J. Herman,et al.  Synergistic activation of functional estrogen receptor (ER)-α by DNA methyltransferase and histone deacetylase inhibition in human ER-α-negative breast cancer cells , 2001 .

[48]  Shadan Ali,et al.  Epigenetic silencing of miR-34a in human prostate cancer cells and tumor tissue specimens can be reversed by BR-DIM treatment. , 2012, American journal of translational research.

[49]  S. Gore,et al.  DNA methyltransferase and histone deacetylase inhibitors in the treatment of myelodysplastic syndromes. , 2008, Seminars in hematology.

[50]  T. Barrette,et al.  ONCOMINE: a cancer microarray database and integrated data-mining platform. , 2004, Neoplasia.

[51]  J. Herman,et al.  Synergistic activation of functional estrogen receptor (ER)-alpha by DNA methyltransferase and histone deacetylase inhibition in human ER-alpha-negative breast cancer cells. , 2001, Cancer research.

[52]  Bernhard O. Palsson,et al.  Cancer cell lines , 1999 .