Dysregulation of MiR-212 Promotes Castration Resistance Through HnRNPH1-Mediated Regulation of AR and AR-V7: Implications for Racial Disparity of Prostate Cancer

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2015 Nov 11

PMID 26553749

Citations 49

Authors

Yijun Yang

Dingwu Jia

Hogyoung Kim

Zakaria Y Abd Elmageed

Amrita Datta

Rodney Davis

Sudesh Srivastav

Krzysztof Moroz

Byron E Crawford

Krishnarao Moparty

Raju Thomas

Robert S Hudson

Stefan Ambs

Asim B Abdel-Mageed

Affiliations

Soon will be listed here.

Abstract

Purpose: The causes of disproportionate incidence and mortality of prostate cancer among African Americans (AA) remain elusive. The purpose of this study was to investigate the mechanistic role and assess clinical utility of the splicing factor heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1) in prostate cancer progression among AA men.

Experimental Design: We employed an unbiased functional genomics approach coupled with suppressive subtractive hybridization (SSH) and custom cDNA microarrays to identify differentially expressed genes in microdissected tumors procured from age- and tumor grade-matched AA and Caucasian American (CA) men. Validation analysis was performed in independent cohorts and tissue microarrays. The underlying mechanisms of hnRNPH1 regulation and its impact on androgen receptor (AR) expression and tumor progression were explored.

Results: Aberrant coexpression of AR and hnRNPH1 and downregulation of miR-212 were detected in prostate tumors and correlate with disease progression in AA men compared with CA men. Ectopic expression of miR-212 mimics downregulated hnRNPH1 transcripts, which in turn reduced expression of AR and its splice variant AR-V7 (or AR3) in prostate cancer cells. hnRNPH1 physically interacts with AR and steroid receptor coactivator-3 (SRC-3) and primes activation of androgen-regulated genes in a ligand-dependent and independent manner. siRNA silencing of hnRNPH1 sensitized prostate cancer cells to bicalutamide and inhibited prostate tumorigenesis in vivo

Conclusions: Our findings define novel roles for hnRNPH1 as a putative oncogene, splicing factor, and an auxiliary AR coregulator. Targeted disruption of the hnRNPH1-AR axis may have therapeutic implications to improve clinical outcomes in patients with advanced prostate cancer, especially among AA men.

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References

Chen C, Kobayashi R, Helfman D . Binding of hnRNP H to an exonic splicing silencer is involved in the regulation of alternative splicing of the rat beta-tropomyosin gene. Genes Dev. 1999; 13(5):593-606. PMC: 316507. DOI: 10.1101/gad.13.5.593. View

Heemers H, Tindall D . Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex. Endocr Rev. 2007; 28(7):778-808. DOI: 10.1210/er.2007-0019. View

Culig Z, Comuzzi B, Steiner H, Bartsch G, Hobisch A . Expression and function of androgen receptor coactivators in prostate cancer. J Steroid Biochem Mol Biol. 2005; 92(4):265-71. DOI: 10.1016/j.jsbmb.2004.10.003. View

Waller A, Sharrard R, Berthon P, Maitland N . Androgen receptor localisation and turnover in human prostate epithelium treated with the antiandrogen, casodex. J Mol Endocrinol. 2000; 24(3):339-51. DOI: 10.1677/jme.0.0240339. View

Leman E, Getzenberg R . Nuclear structure as a source of cancer specific biomarkers. J Cell Biochem. 2007; 104(6):1988-93. PMC: 4281772. DOI: 10.1002/jcb.21363. View

Hodgson M, Astapova I, Hollenberg A, Balk S . Activity of androgen receptor antagonist bicalutamide in prostate cancer cells is independent of NCoR and SMRT corepressors. Cancer Res. 2007; 67(17):8388-95. DOI: 10.1158/0008-5472.CAN-07-0617. View

Barboro P, DArrigo C, Repaci E, Bagnasco L, Orecchia P, Carnemolla B . Proteomic analysis of the nuclear matrix in the early stages of rat liver carcinogenesis: identification of differentially expressed and MAR-binding proteins. Exp Cell Res. 2008; 315(2):226-39. DOI: 10.1016/j.yexcr.2008.10.017. View

Donev R, Doneva T, Bowen W, Sheer D . HnRNP-A1 binds directly to double-stranded DNA in vitro within a 36 bp sequence. Mol Cell Biochem. 2002; 233(1-2):181-5. DOI: 10.1023/a:1015504318726. View

Russo A, Siciliano G, Catillo M, Giangrande C, Amoresano A, Pucci P . hnRNP H1 and intronic G runs in the splicing control of the human rpL3 gene. Biochim Biophys Acta. 2010; 1799(5-6):419-28. DOI: 10.1016/j.bbagrm.2010.01.008. View

10.

Honore B, Baandrup U, Vorum H . Heterogeneous nuclear ribonucleoproteins F and H/H' show differential expression in normal and selected cancer tissues. Exp Cell Res. 2004; 294(1):199-209. DOI: 10.1016/j.yexcr.2003.11.011. View

11.

Cleutjens K, van der Korput H, van Eekelen C, van Rooij H, Faber P, Trapman J . An androgen response element in a far upstream enhancer region is essential for high, androgen-regulated activity of the prostate-specific antigen promoter. Mol Endocrinol. 1997; 11(2):148-61. DOI: 10.1210/mend.11.2.9883. View

12.

Watson P, Chen Y, Balbas M, Wongvipat J, Socci N, Viale A . Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. Proc Natl Acad Sci U S A. 2010; 107(39):16759-65. PMC: 2947883. DOI: 10.1073/pnas.1012443107. View

13.

Powell I, Bock C, Ruterbusch J, Sakr W . Evidence supports a faster growth rate and/or earlier transformation to clinically significant prostate cancer in black than in white American men, and influences racial progression and mortality disparity. J Urol. 2010; 183(5):1792-6. PMC: 3840791. DOI: 10.1016/j.juro.2010.01.015. View

14.

Small D, Nelkin B, Vogelstein B . Nonrandom distribution of repeated DNA sequences with respect to supercoiled loops and the nuclear matrix. Proc Natl Acad Sci U S A. 1982; 79(19):5911-5. PMC: 347020. DOI: 10.1073/pnas.79.19.5911. View

15.

Rauch J, ONeill E, Mack B, Matthias C, Munz M, Kolch W . Heterogeneous nuclear ribonucleoprotein H blocks MST2-mediated apoptosis in cancer cells by regulating A-Raf transcription. Cancer Res. 2010; 70(4):1679-88. PMC: 2880479. DOI: 10.1158/0008-5472.CAN-09-2740. View

16.

Holzmann K, Korosec T, Gerner C, Grimm R, Sauermann G . Identification of human common nuclear-matrix proteins as heterogeneous nuclear ribonucleoproteins H and H' by sequencing and mass spectrometry. Eur J Biochem. 1997; 244(2):479-86. DOI: 10.1111/j.1432-1033.1997.00479.x. View

17.

Powell I, Banerjee M, Novallo M, Sakr W, Grignon D, Wood D . Prostate cancer biochemical recurrence stage for stage is more frequent among African-American than white men with locally advanced but not organ-confined disease. Urology. 2000; 55(2):246-51. DOI: 10.1016/s0090-4295(99)00436-7. View

18.

Wang X, Yang Y, Guo X, Sampson E, Hsu C, Tsai M . Suppression of androgen receptor transactivation by Pyk2 via interaction and phosphorylation of the ARA55 coregulator. J Biol Chem. 2002; 277(18):15426-31. DOI: 10.1074/jbc.M111218200. View

19.

Haiman C, Patterson N, Freedman M, Myers S, Pike M, Waliszewska A . Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet. 2007; 39(5):638-44. PMC: 2638766. DOI: 10.1038/ng2015. View

20.

Wallace T, Prueitt R, Yi M, Howe T, Gillespie J, Yfantis H . Tumor immunobiological differences in prostate cancer between African-American and European-American men. Cancer Res. 2008; 68(3):927-36. DOI: 10.1158/0008-5472.CAN-07-2608. View