Alternative splicing in prostate cancer

Abstract

Androgen receptor (AR) splice variants (AR-Vs) have been implicated in the development and progression of metastatic prostate cancer. AR-Vs are truncated isoforms of the AR, a subset of which lack a ligand-binding domain and remain constitutively active in the absence of circulating androgens, thus promoting cancer cell proliferation. Consequently, AR-Vs have been proposed to contribute not only to resistance to anti-androgen therapies but also to resistance to radiotherapy in patients receiving combination therapy by promoting DNA repair. AR-Vs, such as AR-V7, have been associated with unfavourable clinical outcomes in patients; however, attempts to specifically inhibit or prevent the formation of AR-Vs have, to date, been unsuccessful. Thus, novel therapeutic strategies are desperately needed to address the oncogenic effects of AR-Vs, which can drive lethal forms of prostate cancer. Disruption of alternative splicing through modulation of the spliceosome is one such potential therapeutic avenue; however, our understanding of the biology of the spliceosome and how it contributes to prostate cancer remains incomplete, as reflected in the dearth of spliceosome-targeted therapeutic agents. In this Review, the authors outline the current understanding of the role of the spliceosome in the progression of prostate cancer and explore the therapeutic utility of manipulating alternative splicing to improve patient care.

Dysregulated Alternative Splicing Landscape Identifies Intron Retention as a Hallmark and Spliceosome as a Therapeutic Vulnerability in Aggressive Prostate Cancer

“…We subsequently tested this postulate using spliceosome inhibitors. Several microbial products, including Pladienolide B and its derivative E7107 have been shown to bind and inhibit the SF3B1 complex and manifest anti-cancer activities (12,20). The E7107 compound represented the first-in-class spliceosome inhibitor that underwent phase I clinical trial (66).…”

“…Studies of AR variants, ARv7 in particular, have implicated splicing dysregulation in PCa resistance to ADT/Enza (20). Recently, splicing factor HNRNPL was identified as a dependency for LNCaP cells (70) and SFPQ (i.e., PSF) was reported to promote AR splicing and CRPC cell survival (71).…”

“…This raises an interesting question of whether these alterations are just passenger mutations or they causally contribute to PCa pathogenesis. While direct functional evidence implicating them in PCa biology awaits experimental validation, the involvement of these genes in other types of cancer has been reported (9,10,20). Particularly, splicing dysregulation has been recently proposed as a ‘driver’ of transformation independently of oncogenic processes (17).…”

“…Recently, global analyses of aberrant AS landscape across many human cancer types, including PCa, have been reported using RNA-seq data in TCGA (13,17–19), but these studies generally overlooked PCa and only analyzed pri-PCa, leaving behind life-threatening mCRPC. Furthermore, regarding the functional consequence of splicing dysregulation in PCa, previous studies have mainly focused on a few well-known genes typified by AR and CD44 (20), and the potential biological impact and clinical relevance of global splicing abnormalities in PCa remains unclear. Here, we specifically focus on PCa and provide, to our knowledge, the first comprehensive characterization of the AS landscape during disease development and progression and upon treatment failure.…”

MED19 alters AR occupancy and gene expression in prostate cancer cells, driving MAOA expression and growth under low androgen

“…We found that AR mRNA and protein were unchanged in MED19 LNCaP cells compared to control LNCaP cells under androgen deprivation (Fig 3A and 3B). MED19 overexpression also did not induce expression of AR-V7, a constitutively active splice variant of AR lacking the ligand binding domain that can drive androgen independence in prostate cancer (S4 Fig) [32].…”