VIM-AS1 promotes proliferation and drives enzalutamide resistance in prostate cancer via IGF2BP2-mediated HMGCS1 mRNA stabilization

VIM-AS1, a cancer-specific long non-coding RNA, has been recognized as a pivotal regulator in multiple types of cancer. However, the role of VIM-AS1 in the proliferation and resistance to anti-androgen therapy of LNCaP and C4-2 prostate cancer cells remains to be determined. In the current study, gain-and-loss experiments were used to investigate the effects of VIM-AS on the proliferation and anti-androgen therapy of LNCaP and C4-2 cells. RNA sequencing, RNA pulldown and RNA immunoprecipitation were used to elucidate the underlying mechanism of VIM-AS1 driving prostate progression. It was demonstrated that VIM-AS1 was upregulated in C4-2 cells, an established castration-resistant prostate cancer (CRPC) cell line, compared with in LNCaP cells, an established hormone-sensitive prostate cancer cell line. The present study further demonstrated that VIM-AS1 was positively associated with the clinical stage of prostate cancer. Functionally, overexpression of VIM-AS1 decreased the sensitivity to enzalutamide treatment and enhanced the proliferation of LNCaP cells in vitro, whereas knockdown of VIM-AS1 increased the sensitivity to enzalutamide treatment and reduced the proliferation of C4-2 cells in vitro and in vivo. Mechanistically, 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) was identified as one of the direct downstream targets of VIM-AS1, and VIM-AS1 promoted HMGCS1 expression by enhancing HMGCS1 mRNA stability through a VIM-AS1/insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2)/HMGCS1 RNA-protein complex. Rescue assays indicated that knockdown of HMGCS1 expression ameliorated the increase in proliferation and enzalutamide resistance of prostate cancer cells induced by VIM-AS1 overexpression. Overall, the present study determined the roles and mechanism of the VIM-AS1/IGF2BP2/HMGCS1 axis in regulating proliferation and enzalutamide sensitivity of prostate cancer cells and suggested that VIM-AS1 may serve as a novel therapeutic target for the treatment of patients with CRPC.