Nonconserved miR-608 suppresses prostate cancer progression through RAC2/PAK4/LIMK1 and BCL2L1/caspase-3 pathways by targeting the 3'-UTRs of RAC2/BCL2L1 and the coding region of PAK4.

Abstract

The aim of this study is to investigate the functions and mechanisms of miR‐608 in prostate cancer (PCa). CISH and qRT‐PCR analysis demonstrated that miR‐608 was low expressed in PCa tissues and cells, which was partly attributed to the methylation of CpG island adjacent to the transcription start site (TSS) of miR‐608 gene. Intracellular miR‐608 overexpression inhibited in vivo PCa tumor growth, and suppressed PCa cell proliferation, G2/M transition, and migration in vitro, which was independent of EMT‐associated mechanisms. Then RAC2, a GTPase previously deemed hematopoiesis‐specific but now discovered to exist and play important roles in PCa, was verified by western blot and dual‐luciferase reporter assays to mediate the effects of miR‐608 through RAC2/PAK4/LIMK1/cofilin pathway. MiR‐608 also promoted the apoptosis of PCa cells through BCL2L1/caspase‐3 pathway by targeting the 3′‐UTR of BCL2L1. Moreover, PAK4, the downstream effector of RAC2, was found to be targeted by miR‐608 at the mRNA coding sequence (CDS) instead of the canonical 3′‐UTR. Knocking down RAC2, PAK4, or BCL2L1 with siRNAs reproduced the antiproliferative, mitosis‐obstructive, antimigratory and proapoptotic effects of miR‐608 in PCa cells, which could be attenuated by downregulating miR‐608. In conclusion, miR‐608 suppresses PCa progression, and its activation provides a new therapeutic option for PCa.