miRNA-34b inhibits prostate cancer through demethylation, active chromatin modifications, and AKT pathways

Shahana Majid, Altaf A. Dar, Sharanjot Saini, Varahram Shahryari, Sumit Arora, Mohd Saif Zaman, Inik Chang, Soichiro Yamamura, Yuichiro Tanaka, Takeshi Chiyomaru, Guoren Deng, Rajvir Dahiya

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

Purpose: miRNAs can act as oncomirs or tumor-suppressor miRs in cancer. This study was undertaken to investigate the status and role of miR-34b in prostate cancer. Experimental Design: Profiling of miR-34b was carried out in human prostate cancer cell lines and clinical samples by quantitative real-time PCR and in situ hybridization. Statistical analyses were done to assess diagnostic/prognostic potential. Biological significance was elucidated by carrying out a series of experiments in vitro and in vivo. Results: We report that miR-34b is silenced in human prostate cancer and the mechanism is through CpG hypermethylation. miR-34b directly targeted methyltransferases and deacetylases resulting in a positive feedback loop inducing partial demethylation and active chromatin modifications. miR-34b expression could predict overall and recurrence-free survival such that patients with high miR-34b levels had longer survival. Functionally, miR-34b inhibited cell proliferation, colony formation, migration/invasion, and triggered G 0/G1 cell-cycle arrest and apoptosis by directly targeting the Akt and its downstream proliferative genes. miR-34b caused a decline in the mesenchymal markers vimentin, ZO1, N-cadherin, and Snail with an increase in E-cadherin expression, thus inhibiting epithelial-to-mesenchymal transition. Finally we showed the antitumor effect of miR-34b in vivo. MiR-34b caused a dramatic decrease in tumor growth in nude mice compared with cont-miR. Conclusion: These findings offer new insight into the role of miR-34b in the inhibition of prostate cancer through demethylation, active chromatin modification, and Akt pathways and may provide a rationale for the development of new strategies targeting epigenetic regulation of miRNAs for the treatment of prostate cancer.

Original languageEnglish (US)
Pages (from-to)73-84
Number of pages12
JournalClinical Cancer Research
Volume19
Issue number1
DOIs
StatePublished - Jan 1 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'miRNA-34b inhibits prostate cancer through demethylation, active chromatin modifications, and AKT pathways'. Together they form a unique fingerprint.

  • Cite this

    Majid, S., Dar, A. A., Saini, S., Shahryari, V., Arora, S., Zaman, M. S., Chang, I., Yamamura, S., Tanaka, Y., Chiyomaru, T., Deng, G., & Dahiya, R. (2013). miRNA-34b inhibits prostate cancer through demethylation, active chromatin modifications, and AKT pathways. Clinical Cancer Research, 19(1), 73-84. https://doi.org/10.1158/1078-0432.CCR-12-2952