Androgen-dependent alternative mRNA isoform expression in prostate cancer cells

Abstract

Background: Androgen steroid hormones are key drivers of prostate cancer. Previous work has shown that androgens can drive the expression of alternative mRNA isoforms as well as transcriptional changes in prostate cancer cells. Yet to what extent androgens control alternative mRNA isoforms and how these are expressed and differentially regulated in prostate tumours is unknown. Methods: Here we have used RNA-Seq data to globally identify alternative mRNA isoform expression under androgen control in prostate cancer cells, and profiled the expression of these mRNA isoforms in clinical tissue. Results: Our data indicate androgens primarily switch mRNA isoforms through alternative promoter selection. We detected 73 androgen regulated alternative transcription events, including utilisation of 56 androgen-dependent alternative promoters, 13 androgen-regulated alternative splicing events, and selection of 4 androgen-regulated alternative 3′ mRNA ends. 64 of these events are novel to this study, and 26 involve previously unannotated isoforms. We validated androgen dependent regulation of 17 alternative isoforms by quantitative PCR in an independent sample set. Some of the identified mRNA isoforms are in genes already implicated in prostate cancer (including LIG4, FDFT1 and RELAXIN), or in genes important in other cancers (e.g. NUP93 and MAT2A). Importantly, analysis of transcriptome data from 497 tumour samples in the TGCA prostate adenocarcinoma (PRAD) cohort identified 13 mRNA isoforms (including TPD52, TACC2 and NDUFV3) that are differentially regulated in localised prostate cancer relative to normal tissue, and 3 ( OSBPL1A, CLK3 and TSC22D3) which change significantly with Gleason grade and tumour stage. Conclusions: Our findings dramatically increase the number of known androgen regulated isoforms in prostate cancer, and indicate a highly complex response to androgens in prostate cancer cells that could be clinically important.

Androgen-regulated transcription ofESRP2drives alternative splicing patterns in prostate cancer

“…The data presented here imply that androgens also have an important role in controlling splicing patterns, particularly those that relate to epithelial functions. Previous studies identified just a small number of alternative exons that are controlled by androgens in prostate cancer cells, none of which overlapped with the current study (9,11). We suggest that an important reason for this discrepancy is because previously splicing patterns were monitored after 24 hours of androgen exposure.…”

“…The roles of both androgens and the AR in transcription have been intensively investigated. However, androgens and the AR also regulate alternative pre-mRNA splicing through still largely unknown mechanisms (6)(7)(8)(9)(10)(11). This represents a very important knowledge gap: alternative splicing patterns in cancer cells can generate protein isoforms with different biological functions (12), and is a key process in the generation of biological heterogeneity in prostate cancer (13,14).…”

“…The estrogen and progesterone steroid nuclear hormone receptors control splicing via recruitment of alternative splicing regulators (including the RNA helicases Ddx5 and Ddx17) (7,8,26), and by changing RNA polymerase II extension rates and chromatin structure to affect splice site selection (27,28). Steroid hormones can also drive selection of alternative promoters to include different upstream exons in mRNAs (9,10). However, to what extent the above mechanisms may contribute to androgen-mediated splicing is largely unknown.…”

Pan-cancer driver copy number alterations identified by joint expression/CNA data analysis

“… 18 , 19 APPBP2, TRIM37 54 , 55 GPS1 GPS1, ANAPC11, DUS1L, RFNG, OXLD1, MRPL12, LRRC45, CENPX, ASPSCR1, CCDC137, FAAP100, CEP131, MCRIP1, DCXR, PCYT2, SIRT7 17q25.3 Ref. 19 DUS1L 56 POLR2I POLR2I, TIMM50, MRPS12, RBM42, C19orf47, NFKBIB, TBCB, SDHAF1, YIF1B, EXOSC5 19q13.12 Neither Pancreatic cancer 57 and bladder cancer 58 YIF1B 59 ZNF420 ZNF420, ZNF461, ZNF567, ZNF383, ZNF566, ZFP30, ZNF260, ZNF585A, ZNF570, ZNF527, ZNF571, ZNF569, ZFP14, ZNF568 19q13.12 Neither Pancreatic cancer 57 and bladder cancer 58 ZFP14 60 HSPBP1 HSPBP1, ZNF865, ZNF579, ZNF787, EPN1, FIZ1, ZNF444, ZNF524, ZNF580, ZNF784, RPL28, ZNF581 19q13.42 Refs. 18 , 19 RPL28 61 ZNF134 ZNF134, ZNF304, ZNF551, ZNF776, ZNF17 19q13.43 Refs.…”

The potential disruption of estrogen and androgen homeostasis and adipocyte differentiation by metabolites of common airborne polychlorinated biphenyls

“…Disruptions of the androgen system have been linked to the development of hormone-dependent prostate cancer, systemic autoimmune disorders, diabetes mellitus, infertility, and other health issues [187,[191][192][193][194][195]. DHEA-deficiency or excess could impact its role in regulating adipokine expression and secretion [196].…”