The miR-361-3p increases enzalutamide (Enz) sensitivity via targeting the ARv7 and MKNK2 to better suppress the Enz-resistant prostate cancer

Bianjiang Liu,Min Tang,Yuanjie Niu,Zengjun Wang,Chawnshang Chang,Chao Liang,Chi-Ping Huang,Yin Sun

doi:10.1038/s41419-020-02932-w

Abstract

The androgen receptor splicing variant 7 (ARv7) that lacks the ligand-binding domain is increasingly considered as a key player leading to enzalutamide (Enz) resistance in patients with prostate cancer (PCa). However, the detailed mechanisms of how ARv7 expression is regulated and whether it also needs other factors to induce maximal Enz resistance remain unclear. Here, we identified a microRNA, miR-361-3p, whose expression is lower in patients with recurrent PCa, could function via binding to the 3′UTR of ARv7, but not the wild type of AR, to suppress its expression to increase the Enz sensitivity. Importantly, we found that miR-361-3p could also bind to the 3′UTR of MAP kinase-interacting serine/threonine kinase 2 (MKNK2) to suppress its expression to further increase the Enz sensitivity. In turn, the increased Enz can then function via a feedback mechanism through altering the HIF-2α/VEGFA signaling to suppress the expression of miR-361-3p under hypoxia conditions. Preclinical studies using an in vivo mouse model with orthotopically xenografted CWR22Rv1 cells demonstrated that combining the Enz with the small molecule miR-361-3p would result in better suppression of the Enz-resistant PCa tumor progression. Together, these preclinical studies demonstrate that miR-361-3p can function via suppressing the expression of ARv7 and MKNK2 to maximally increase the Enz sensitivity, and targeting these newly identified Enz/miR-361-3p/ARv7 and/or Enz/miR-361-3p/MKNK2 signals with small molecules may help in the development of novel therapies to better suppress the CRPC in patients that already have developed the Enz resistance.

Highlights

Prostate cancer (PCa) is the leading cause of cancerrelated deaths among males in western countries[1], and androgen-deprivation therapy (ADT) with antiandrogens remains the standard therapy to treat the castration-resistant prostate cancer (PCa) (CRPC) patients
As androgen receptor splicing variant 7 (ARv7) has a unique 3’UTR compared to the full-length androgen receptor (AR) (see the website (Fig. 1a), we were interested to see if this unique 3′ untranslated regions (3′UTR) in the ARv7 may contribute to its induction of the Enz resistance
(see figure on previous page) Fig. 1 The miRNA-361-3p suppressed androgen receptor splicing variant 7 (ARv7) expression and prostate cancer (PCa) formation. a ARv7 has its unique 3′UTR compared to the 3′UTR of full-length AR (fAR). b The selected tumor suppressor miRNA has binding sites to the ARv7 3′UTR, and is differentially expressed in recurrent tumors. c Western blot analysis shows that adding miR-361-3p suppresses ARv7 protein expression in CWR22Rv1 cells

Summary

Introduction

Prostate cancer (PCa) is the leading cause of cancerrelated deaths among males in western countries[1], and androgen-deprivation therapy (ADT) with antiandrogens remains the standard therapy to treat the castration-resistant PCa (CRPC) patients. ADT, with development of antiandrogen resistance, even though the androgen receptor (AR) continues to function[2,3]. Enz resistance eventually may occur due to multiple mechanisms[8,9,10,11], including recent clinical studies showing that Enz might induce the expression of some AR-splice variants[3,12,13,14,15]. The AR-splice variant 7 (ARv7) is the most studied AR variant that has clear human clinical data showing its positive linkage to the development of Enz resistance[16,17,18,19]. The detailed mechanism of how ARv7 is Official journal of the Cell Death Differentiation Association

Methods

Results

Conclusion