Epigenetically altered miR-193b targets cyclin D1 in prostate cancer

Cancer Med. 2015 Sep;4(9):1417-25. doi: 10.1002/cam4.486. Epub 2015 Jul 1.


Micro-RNAs (miRNA) are important regulators of gene expression and often differentially expressed in cancer and other diseases. We have previously shown that miR-193b is hypermethylated in prostate cancer (PC) and suppresses cell growth. It has been suggested that miR-193b targets cyclin D1 in several malignancies. Here, our aim was to determine if miR-193b targets cyclin D1 in prostate cancer. Our data show that miR-193b is commonly methylated in PC samples compared to benign prostate hyperplasia. We found reduced miR-193b expression (P < 0.05) in stage pT3 tumors compared to pT2 tumors in a cohort of prostatectomy specimens. In 22Rv1 PC cells with low endogenous miR-193b expression, the overexpression of miR-193b reduced CCND1 mRNA levels and cyclin D1 protein levels. In addition, the exogenous expression of miR-193b decreased the phosphorylation level of RB, a target of the cyclin D1-CDK4/6 pathway. Moreover, according to a reporter assay, miR-193b targeted the 3'UTR of CCND1 in PC cells and the CCND1 activity was rescued by expressing CCND1 lacking its 3'UTR. Immunohistochemical analysis of cyclin D1 showed that castration-resistant prostate cancers have significantly (P = 0.0237) higher expression of cyclin D1 compared to hormone-naïve cases. Furthermore, the PC cell lines 22Rv1 and VCaP, which express low levels of miR-193b and high levels of CCND1, showed significant growth retardation when treated with a CDK4/6 inhibitor. In contrast, the inhibitor had no effect on the growth of PC-3 and DU145 cells with high miR-193b and low CCND1 expression. Taken together, our data demonstrate that miR-193b targets cyclin D1 in prostate cancer.

Keywords: Cyclin D1; micro-RNA; prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Cell Line, Tumor
  • Cyclin D1 / genetics*
  • DNA Methylation
  • Epigenesis, Genetic*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Male
  • MicroRNAs / genetics*
  • Neoplasm Grading
  • Neoplasm Recurrence, Local
  • Neoplasm Staging
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology*
  • Prostatic Neoplasms / surgery
  • RNA Interference*
  • RNA, Messenger / genetics


  • 3' Untranslated Regions
  • MIRN193 microRNA, human
  • MicroRNAs
  • RNA, Messenger
  • Cyclin D1