Open AccessEpigenetically altered miR‐193b targets cyclin D1 in prostate cancer
Author(s) -
Kaukoniemi Kirsi M.,
Rauhala Hanna E.,
Scaravilli Mauro,
Latonen Leena,
Annala Matti,
Vessella Robert L.,
Nykter Matti,
Tammela Teuvo L. J.,
Visakorpi Tapio
Publication year - 2015
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.486
Subject(s) - cyclin d1 , du145 , prostate cancer , cancer research , microrna , cancer , biology , prostate , cyclin d , cell growth , cyclin b , cell cycle , lncap , gene , genetics
Micro‐ RNA s (mi RNA ) 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 pT 3 tumors compared to pT 2 tumors in a cohort of prostatectomy specimens. In 22Rv1 PC cells with low endogenous miR‐193b expression, the overexpression of miR‐193b reduced CCND 1 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‐ CDK 4/6 pathway. Moreover, according to a reporter assay, miR‐193b targeted the 3’ UTR of CCND 1 in PC cells and the CCND 1 activity was rescued by expressing CCND 1 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 VC aP, which express low levels of miR‐193b and high levels of CCND 1 , showed significant growth retardation when treated with a CDK 4/6 inhibitor. In contrast, the inhibitor had no effect on the growth of PC ‐3 and DU 145 cells with high miR‐193b and low CCND 1 expression. Taken together, our data demonstrate that miR‐193b targets cyclin D1 in prostate cancer.