Abstract
Mechanisms by which non-coding RNAs contribute to the progression of hormone-sensitive prostate cancer (PCa) (HSPC) to castration-resistant PCa (CRPC) remain largely unknown. We previously showed that microRNA-221/222 is up-regulated in CRPC and plays a critical role in modulating androgen receptor function during CRPC development. With further investigation, we characterized a putative promoter region located 23.3 kb upstream of the miR-221/222 gene, and this promoter is differentially activated in CRPC LNCaP-Abl cells, leading to the up-regulation of miR-221/222. Upon promoter activation, a set of polyadenylated long non-coding RNA (lncRNA) MIR222HGs was transcribed from this promoter region. Over-expression of these MIR222HGs increased androgen-independent cell growth and repressed the expression of androgen receptor-regulated dihydrotestosterone (DHT)-induced KLK3, TMPRSS2, and FKBP5 in HSPC LNCaP cells, hallmarks of the CRPC phenotype. Clinically, increased expression of MIR222HG is associated with PCa progression to CRPC. In primary tumors, expression levels of MIR222HG and miR-221/222 inversely correlate with Gleason score and androgen receptor (AR) pathway activity. Interestingly, MIR222HG is Argonaute 2-bound and its expression is Dicer 1-dependent, suggesting its functional association with the RNA-induced silencing complex. Further studies led to the hypothesis that MIR222HG may potentially affect miR-mediated expression silencing, subsequently leading to AR reprogramming. Our study highlights an essential role of a non-coding RNA in CRPC development and that differential activation of a single promoter can up-regulate two different types of non-coding RNAs, miR-221/222 and lncRNA MIR222HG, in CRPC. Additionally, this study reveals a novel function of lncRNAs as a modulator of Argonaute-mediated RNA-induced silencing complex.
Highlights
Prostate cancer (PCa) is the most common noncutaneous malignancy diagnosed in American men and the second leading cause of cancer mortality in men[1].Androgens and the androgen receptor (AR) play crucial roles in PCa development and progression
Our study suggests that up-regulation of miR221/222 and long non-coding RNA (lncRNA) MIR222HG expression in castration-resistant PCa (CRPC) are most likely driven by the activation of the same promoter and both of them are involved in the progression from hormone-sensitive prostate cancer (HSPC) to CRPC
We previously showed that miR-221/222 is frequently over-expressed in CRPC tumors, participating in the CRPC development
Summary
Prostate cancer (PCa) is the most common noncutaneous malignancy diagnosed in American men and the second leading cause of cancer mortality in men[1]. Androgens and the androgen receptor (AR) play crucial roles in PCa development and progression. Androgen deprivation therapy (ADT) remains a key treatment for advanced PCa. Most hormone-sensitive PCa patients initially respond to ADT; most patients develop resistance to ADT and progress to the lethal castration-resistant PCa (CRPC)[2,3]. PCa cells utilize a variety of AR-dependent and AR-independent pathways to survive in an androgen-depleted environment during CRPC progression. Many studies have shown that CRPC is frequently characterized by altered AR expression and
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