Androgen-regulated processing of the oncomir miR-27a, which targets Prohibitin in prostate cancer.

MicroRNAs (miRs) play an important role in the development of many complex human diseases and may have tumour suppressor or oncogenic (oncomir) properties. Prostate cancer is initially an androgen-driven disease, and androgen receptor (AR) remains a key driver of growth even in castration-resistant tumours. However, AR-mediated oncomiR pathways remain to be elucidated. We demonstrate that miR-27a is an androgen-regulated oncomir in prostate cancer, acting via targeting the tumour suppressor and AR corepressor, Prohibitin (PHB). Increasing miR-27a expression results in reduced PHB mRNA and protein levels, and increased expression of AR target genes and prostate cancer cell growth. This involves a novel mechanism for androgen-mediated miR regulation, whereby AR induces a transient increase in miR-23a27a24-2 transcription, but more significantly accelerates processing of the primiR-23a27a24-2 cluster. Androgens therefore regulate miR-27a expression both transcriptionally (via AR binding to the cluster promoter) and post-transcriptionally (accelerating primiR processing to the mature form). We further show that a miR-27a anti-sense oligonucleotide, by opposing the effects of mir-27a, has therapeutic potential in prostate cancer.

[1]  B. Spencer‐Dene,et al.  FUS/TLS is a novel mediator of androgen-dependent cell-cycle progression and prostate cancer growth. , 2011, Cancer research.

[2]  N. Saini,et al.  Cooperative and individualistic functions of the microRNAs in the miR-23a~27a~24-2 cluster and its implication in human diseases , 2010, Molecular Cancer.

[3]  M. Ittmann,et al.  The function of microRNAs, small but potent molecules, in human prostate cancer , 2010, Prostate Cancer and Prostatic Diseases.

[4]  A. Jemal,et al.  Cancer Statistics, 2010 , 2010, CA: a cancer journal for clinicians.

[5]  S. Safe,et al.  MicroRNA-27a Indirectly Regulates Estrogen Receptor {alpha} Expression and Hormone Responsiveness in MCF-7 Breast Cancer Cells. , 2010, Endocrinology.

[6]  S. Pfeffer,et al.  Post-transcriptional regulation of miR-27 in murine cytomegalovirus infection. , 2010, RNA.

[7]  S. Shenouda,et al.  MicroRNA function in cancer: oncogene or a tumor suppressor? , 2009, Cancer and Metastasis Reviews.

[8]  B. Spencer‐Dene,et al.  Manipulating prohibitin levels provides evidence for an in vivo role in androgen regulation of prostate tumours , 2009, Endocrine-related cancer.

[9]  V. Scaria,et al.  Upregulation of miR-23a∼27a∼24-2 Cluster Induces Caspase-Dependent and -Independent Apoptosis in Human Embryonic Kidney Cells , 2009, PloS one.

[10]  Min Liu,et al.  MicroRNA-27a functions as an oncogene in gastric adenocarcinoma by targeting prohibitin. , 2009, Cancer letters.

[11]  Elodie Portales-Casamar,et al.  Transcriptional repression of microRNA genes by PML-RARA increases expression of key cancer proteins in acute promyelocytic leukemia. , 2009, Blood.

[12]  Jinjun Li,et al.  Upregulation of miR‐23a∼27a∼24 decreases transforming growth factor‐beta‐induced tumor‐suppressive activities in human hepatocellular carcinoma cells , 2008, International journal of cancer.

[13]  George A. Calin,et al.  Expression of microRNAs and protein‐coding genes associated with perineural invasion in prostate cancer , 2008, The Prostate.

[14]  C. Tepper,et al.  microRNAs and prostate cancer , 2008, Journal of cellular and molecular medicine.

[15]  Jae Hoon Kim,et al.  MicroRNA Expression Profiles in Serous Ovarian Carcinoma , 2008, Clinical Cancer Research.

[16]  D. Tindall,et al.  FOXOs, cancer and regulation of apoptosis , 2008, Oncogene.

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

[18]  T. Golub,et al.  MicroRNA expression signatures accurately discriminate acute lymphoblastic leukemia from acute myeloid leukemia , 2007, Proceedings of the National Academy of Sciences.

[19]  Stephen Safe,et al.  The oncogenic microRNA-27a targets genes that regulate specificity protein transcription factors and the G2-M checkpoint in MDA-MB-231 breast cancer cells. , 2007, Cancer research.

[20]  Anton J. Enright,et al.  Genomic analysis of human microRNA transcripts , 2007, Proceedings of the National Academy of Sciences.

[21]  T. Tammela,et al.  MicroRNA expression profiling in prostate cancer. , 2007, Cancer research.

[22]  R. Scott,et al.  The 3′ untranslated region C > T polymorphism of prohibitin is a breast cancer risk modifier in Polish women carrying a BRCA1 mutation , 2007, Breast Cancer Research and Treatment.

[23]  D. Dart,et al.  Prohibitin, a protein downregulated by androgens, represses androgen receptor activity , 2007, Oncogene.

[24]  Yonghong Xiao,et al.  FoxOs Are Lineage-Restricted Redundant Tumor Suppressors and Regulate Endothelial Cell Homeostasis , 2007, Cell.

[25]  P. Rennie,et al.  Short hairpin RNA knockdown of the androgen receptor attenuates ligand-independent activation and delays tumor progression. , 2006, Cancer research.

[26]  C. Croce,et al.  MicroRNA signatures in human cancers , 2006, Nature Reviews Cancer.

[27]  F. Slack,et al.  Oncomirs — microRNAs with a role in cancer , 2006, Nature Reviews Cancer.

[28]  L. Murphy,et al.  The Prohibitins: emerging roles in diverse functions , 2006, Journal of cellular and molecular medicine.

[29]  C. Croce,et al.  A microRNA expression signature of human solid tumors defines cancer gene targets , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Minchen Chien,et al.  Prognostic Values of microRNAs in Colorectal Cancer , 2006, Biomarker insights.

[31]  C. Croce,et al.  miR-15 and miR-16 induce apoptosis by targeting BCL2. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Volker Brinkmann,et al.  Prohibitin is required for Ras-induced Raf–MEK–ERK activation and epithelial cell migration , 2005, Nature Cell Biology.

[33]  F. Slack,et al.  RAS Is Regulated by the let-7 MicroRNA Family , 2005, Cell.

[34]  S. Balk,et al.  The Androgen Receptor Recruits Nuclear Receptor CoRepressor (N-CoR) in the Presence of Mifepristone via Its N and C Termini Revealing a Novel Molecular Mechanism for Androgen Receptor Antagonists* , 2005, Journal of Biological Chemistry.

[35]  B. Cullen,et al.  Recognition and cleavage of primary microRNA precursors by the nuclear processing enzyme Drosha , 2005, The EMBO journal.

[36]  Sanghyuk Lee,et al.  MicroRNA genes are transcribed by RNA polymerase II , 2004, The EMBO journal.

[37]  E. Lam,et al.  Androgens target prohibitin to regulate proliferation of prostate cancer cells , 2004, Oncogene.

[38]  C. Croce,et al.  Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[39]  S. Chellappan,et al.  Prohibitin Induces the Transcriptional Activity of p53 and Is Exported from the Nucleus upon Apoptotic Signaling* , 2003, Journal of Biological Chemistry.

[40]  J. C. Ghosh,et al.  Regulation of Androgen Receptor Activity by the Nuclear Receptor Corepressor SMRT* , 2003, The Journal of Biological Chemistry.

[41]  J. Padmanabhan,et al.  Prohibitin co-localizes with Rb in the nucleus and recruits N-CoR and HDAC1 for transcriptional repression , 2002, Oncogene.

[42]  J. Wong,et al.  p300 Requires Its Histone Acetyltransferase Activity and SRC-1 Interaction Domain To Facilitate Thyroid Hormone Receptor Activation in Chromatin , 2000, Molecular and Cellular Biology.

[43]  Helmut Klocker,et al.  Rapid signalling by androgen receptor in prostate cancer cells , 1999, Oncogene.

[44]  Walter Neupert,et al.  Prohibitins Regulate Membrane Protein Degradation by the m-AAA Protease in Mitochondria , 1999, Molecular and Cellular Biology.

[45]  C. Allis,et al.  Steroid receptor coactivator-1 is a histone acetyltransferase , 1997, Nature.

[46]  D. J. Jamieson,et al.  The prohibitin family of mitochondrial proteins regulate replicative lifespan , 1997, Current Biology.

[47]  M. Montminy,et al.  Role of CBP/P300 in nuclear receptor signalling , 1996, Nature.

[48]  E. Jupe,et al.  Prohibitin in breast cancer cell lines: loss of antiproliferative activity is linked to 3' untranslated region mutations. , 1996, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[49]  M. Reth,et al.  The IgM antigen receptor of B lymphocytes is associated with prohibitin and a prohibitin‐related protein. , 1994, The EMBO journal.

[50]  M. Skolnick,et al.  The human prohibitin gene located on chromosome 17q21 is mutated in sporadic breast cancer. , 1992, Cancer research.

[51]  H. Okayama,et al.  High-efficiency transformation of mammalian cells by plasmid DNA. , 1987, Molecular and cellular biology.

[52]  F. Hamdy,et al.  Platinum Priority – Collaborative Review – Prostate Cancer MicroRNA in Prostate , Bladder , and Kidney Cancer : A Systematic Review , 2011 .

[53]  N. Kyprianou,et al.  Prohibitin regulates TGF‐β induced apoptosis as a downstream effector of smad‐dependent and ‐independent signaling , 2010, The Prostate.

[54]  É. Várallyay,et al.  MicroRNA detection by northern blotting using locked nucleic acid probes , 2008, Nature Protocols.

[55]  V. Kim,et al.  In vitro and in vivo assays for the activity of Drosha complex. , 2007, Methods in enzymology.

[56]  B. Cullen,et al.  Sequence requirements for micro RNA processing and function in human cells. , 2003, RNA.

[57]  T. Visakorpi,et al.  Androgen receptor gene and hormonal therapy failure of prostate cancer. , 1998, The American journal of pathology.