Androgen receptor and its splice variant, AR-V7, differentially induce mRNA splicing in prostate cancer cells

AbstractProstate cancer (PCa) is dependent on the androgen receptor (AR). Advanced PCa is treated with an androgen deprivation therapy-based regimen; tumors develop resistance, although they typically remain AR-dependent. Expression of constitutively active AR variants lacking the ligand-binding domain including the variant AR-V7 contributes to this resistance. AR and AR-V7, as transcription factors, regulate many of the same genes, but also have unique activities. In this study, the capacity of the two AR isoforms to regulate splicing was examined. RNA-seq data from models that endogenously express AR and express AR-V7 in response to doxycycline were used. Both AR isoforms induced multiple changes in splicing and many changes were isoform-specific. Analyses of two endogenous genes, PGAP2 and TPD52, were performed to examine differential splicing. A novel exon that appears to be a novel transcription start site was preferentially induced by AR-V7 in PGAP2 although it is induced to a lesser extent by AR. The previously described AR induced promoter 2 usage that results in a novel protein derived from TPD52 (PrLZ) was not induced by AR-V7. AR, but not AR-V7, bound to a site proximal to promoter 2, and induction was found to depend on FOXA1.

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Second-Generation HSP90 Inhibitor Onalespib Blocks mRNA Splicing of Androgen Receptor Variant 7 in Prostate Cancer Cells

Cancer Research ◽

10.1158/0008-5472.can-15-2186 ◽

2016 ◽

Vol 76 (9) ◽

pp. 2731-2742 ◽

Cited By ~ 49

Author(s):

Roberta Ferraldeschi ◽

Jonathan Welti ◽

Marissa V. Powers ◽

Wei Yuan ◽

Tomoko Smyth ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Cells ◽

Second Generation ◽

Hsp90 Inhibitor ◽

Mrna Splicing ◽

Prostate Cancer Cells

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Abstract 4556: AR intragenic rearrangement and altered androgen receptor mRNA splicing in castration-resistant prostate cancer

10.1158/1538-7445.am2011-4556 ◽

2011 ◽

Author(s):

Yingming Li ◽

Majid Alsagabi ◽

Ahmed Tewfik ◽

Scott M. Dehm

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Mrna Splicing ◽

Castration Resistant Prostate Cancer ◽

Receptor Mrna ◽

Castration Resistant

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Author Correction: Androgen receptor and its splice variant, AR-V7, differentially induce mRNA splicing in prostate cancer cells

Scientific Reports ◽

10.1038/s41598-021-90079-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Manjul Rana ◽

Jianrong Dong ◽

Matthew J. Robertson ◽

Paul Basil ◽

Cristian Coarfa ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Cells ◽

Splice Variant ◽

Mrna Splicing ◽

Prostate Cancer Cells

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Estrogen receptor β exerts tumor suppressive effects in prostate cancer through repression of androgen receptor activity

10.1101/850180 ◽

2019 ◽

Cited By ~ 1

Author(s):

Surendra Chaurasiya ◽

Scott Widmann ◽

Cindy Botero ◽

Chin-Yo Lin ◽

Anders M. Strom ◽

...

Keyword(s):

Prostate Cancer ◽

Estrogen Receptor ◽

Androgen Receptor ◽

Estrogen Receptor Β ◽

Rna Seq ◽

Protein Levels ◽

Synthetic Ligand ◽

Androgen Receptor Activity ◽

Mutant Phenotypes ◽

Prostate Epithelium

AbstractEstrogen receptor β (ERβ) was first identified in the rodent prostate and is abundantly expressed in human and rodent prostate epithelium, stroma, immune cells and endothelium of the blood vessels. In the prostates of mice with inactivated ERβ, mutant phenotypes include epithelial hyperplasia and increased expression of androgen receptor (AR)-regulated genes, most of which are also upregulated in prostate cancer (PCa). ERβ is expressed in both basal and luminal cells in the prostate while AR is expressed in luminal but not in the basal cell layer which harbors the prostate stem cells. To investigate the mechanisms of action of ERβ and its potential cross-talk with AR, we used RNA-seq to study the effects of estradiol or the synthetic ligand, LY3201, in AR-positive LNCaP PCa cells which had been engineered to express ERβ. Transcriptomic analysis indicated relatively few changes in gene expression with ERβ overexpression, but robust responses following ligand treatments. There is significant overlap of responsive genes between the two ligands, as well as ligand-specific alterations. Gene set analysis of down-regulated genes identified an enrichment of androgen-responsive genes, such as FKBP5, CAMKK2, and TBC1D4. Consistently, AR transcript, protein levels, and transcriptional activity were down-regulated following ERβ activation. In agreement with this, we find that the phosphorylation of the CAMKK2 target, AMPK, was repressed by ligand-activated ERβ. Down-regulation of TBC1D4, a major regulator of glucose uptake in prostate, indicates that ERβ is changing glucose metabolism in the prostate. These findings suggest that ERβ-mediated signaling pathways are involved in the negative regulation of AR expression and activity, thus supporting a tumor suppressive role for ERβ in PCa.

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Characterization of kinase gene expression and splicing profile in prostate cancer with RNA-Seq data

10.1101/061085 ◽

2016 ◽

Author(s):

Huijuan Feng ◽

Tingting Li ◽

Xuegong Zhang

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Alternative Splicing ◽

Differential Expression ◽

Functional Enrichment ◽

Cancer Development ◽

Rna Seq ◽

Differential Splicing ◽

Kinase Gene ◽

Isoform Switching

AbstractBackgroundAlternative splicing is a ubiquitous post-transcriptional process in most eukaryotic genes. Aberrant splicing isoforms and abnormal isoform ratios can contribute to cancer development. Kinase genes are key regulators of various cellular processes. Many kinases are found to be oncogenic and have been intensively investigated in the study of cancer and drugs. RNA-Seq provides a powerful technology for genome-wide study of alternative splicing in cancer besides the conventional gene expression profiling. But this potential has not been fully demonstrated yet.MethodsHere we characterized the transcriptome profile of prostate cancer using RNA-Seq data from viewpoints of both differential expression and differential splicing, with an emphasis on kinase genes and their splicing variations. We built up a pipeline to conduct differential expression and differential splicing analysis. Further functional enrichment analysis was performed to explore functional interpretation of the genes. With focus on kinase genes, we performed kinase domain analysis to identify the functionally important candidate kinase gene in prostate cancer. We further calculated the expression level of isoforms to explore the function of isoform switching of kinase genes in prostate cancer.ResultsWe identified distinct gene groups from differential expression and splicing analysis, which suggested that alternative splicing adds another level to gene expression regulation. Enriched GO terms of differentially expressed and spliced kinase genes were found to play different roles in regulation of cellular metabolism. Function analysis on differentially spliced kinase genes showed that differentially spliced exons of these genes are significantly enriched in protein kinase domains. Among them, we found that gene CDK5 has isoform switching between prostate cancer and benign tissues, which may affect cancer development by changing androgen receptor (AR) phosphorylation. The observation was validated in another RNA-Seq dataset of prostate cancer cell lines.ConclusionsOur work characterized the expression and splicing profile of kinase genes in prostate cancer and proposed a hypothetical model on isoform switching of CDK5 and AR phosphorylation in prostate cancer. These findings bring new understanding to the role of alternatively spliced kinases in prostate cancer and demonstrate the use of RNA-Seq data in studying alternative splicing in cancer.

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