Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer

Munkley, Jennifer; Li, Ling; Krishnan, Subha; Hysenaj, Gerald; Scott, Emma; Dalgliesh, Caroline; Oo, Htoo Zarni; Maia, Teresa; Cheung, Kathleen; Ehrmann, Ingrid; Livermore, Karen E.; Zielińska, Hanna; Thompson, Oliver; Knight, Bridget; McCullagh, Paul; McGrath, John; Crundwell, Malcolm; Harries, Lorna W.; Daugaard, Mads; Cockell, Simon; Barbosa‐Morais, Nuno L.; Oltean, Sebastian; Elliott, David

doi:10.7554/elife.47678

Cited by 52 publications

(37 citation statements)

References 80 publications

(118 reference statements)

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“…This suggests that pharmacological manipulation of AR may alter splicing by regulating expression and binding of ESRP1/2 around spliced exons. Consistent with our findings, Munkley et al, recently published their findings suggesting that androgen stimulation induces splicing switches in ESRP2-controlled mRNA isoforms [43]. We also inquired whether AR-axis may regulate splicing by a nontranscriptional mechanism.…”

Section: Direct Genomic Inhibition Of Ar In Prostate Cancer Cells Indsupporting

confidence: 90%

“…Munkley et al recently used the genomic knockdown of ESRPs to identify global splicing changes associated with ESRPs in prostate cancer cells. They also found that a subset of ESRP1/2 regulated exons were also regulated by androgen treatment [43]. However, the study did not address whether or not AR-axis induces global splicing changes in prostate cancer cells beyond those regulated by ESRPs.…”

Section: Discussionmentioning

confidence: 90%

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Androgen receptor signaling regulates the transcriptome of prostate cancer cells by modulating global alternative splicing

et al. 2020

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Androgen receptor (AR), is a transcription factor and a member of a hormone receptor superfamily. AR plays a vital role in the progression of prostate cancer and is a crucial target for therapeutic interventions. While the majority of advanced-stage prostate cancer patients will initially respond to the androgen deprivation, the disease often progresses to castrate-resistant prostate cancer (CRPC). Interestingly, CRPC tumors continue to depend on hyperactive AR signaling and will respond to potent second-line antiandrogen therapies, including bicalutamide (CASODEX®) and enzalutamide (XTANDI®). However, the progression-free survival rate for the CRPC patients on antiandrogen therapies is only 8–19 months. Hence, there is a need to understand the mechanisms underlying CRPC progression and eventual treatment resistance. Here, we have leveraged next-generation sequencing and newly developed analytical methodologies to evaluate the role of AR signaling in regulating the transcriptome of prostate cancer cells. The genomic and pharmacologic stimulation and inhibition of AR activity demonstrates that AR regulates alternative splicing within cancer-relevant genes. Furthermore, by integrating transcriptomic data from in vitro experiments and in prostate cancer patients, we found that a significant number of AR-regulated splicing events are associated with tumor progression. For example, we found evidence for an inadvertent AR-antagonist-mediated switch in IDH1 and PL2G2A isoform expression, which is associated with a decrease in overall survival of patients. Mechanistically, we discovered that the epithelial-specific splicing regulators (ESRP1 and ESRP2), flank many AR-regulated alternatively spliced exons. And, using 2D invasion assays, we show that the inhibition of ESRPs can suppress AR-antagonist-driven tumor invasion. Our work provides evidence for a new mechanism by which AR alters the transcriptome of prostate cancer cells by modulating alternative splicing. As such, our work has important implications for CRPC progression and development of resistance to treatment with bicalutamide and enzalutamide.

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Section: Direct Genomic Inhibition Of Ar In Prostate Cancer Cells Indsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 90%

Androgen receptor signaling regulates the transcriptome of prostate cancer cells by modulating global alternative splicing

et al. 2020

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“…We have shown that ESRP1, though an ESRP2 paralogue, is not hypermethylated in WTs ( figure 2B, C), suggesting that ESRP1 and ESRP2 may have different biological functions and are regulated differently in some instances. Similarly, a recent paper (68) has reported that only ESRP2 and not ESRP1 is regulated by androgens, with important implications in prostate cancer progression.…”

Section: Discussionmentioning

confidence: 82%

The epithelial splicing regulatorESRP2is epigenetically repressed by DNA hypermethylation in Wilms tumour and acts as a tumour suppressor

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Moriarty

et al. 2020

Preprint

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Wilms tumour (WT), a childhood kidney cancer with embryonal origins, has been extensively characterised for genetic and epigenetic alterations, but a proportion of WTs still lack identifiable abnormalities. To uncover DNA methylation changes critical for WT pathogenesis, we compared the epigenome of fetal kidney with two WT cell lines, using methyl-CpG immunoprecipitation. We filtered our results to remove common cancer-associated epigenetic changes, and to enrich for genes involved in early kidney development. This identified four candidate genes that were hypermethylated in WT cell lines compared to fetal kidney, of which ESRP2 (epithelial splicing regulatory protein 2), was the most promising gene for further study. ESRP2 was commonly repressed by DNA methylation early in WT development (in nephrogenic rests) and could be reactivated by DNA methyltransferase inhibition in WT cell lines. When ESRP2 was expressed in WT cell lines, it acted as an inhibitor of cellular proliferation in vitro and in vivo it suppressed tumour growth of orthotopic xenografts in nude mice. RNA-seq of the ESRP2-expressing WT cell lines identified several novel splicing targets, in addition to well-characterised targets of ESRP2. One of these targets, LEF1, is a component of the Wnt signalling pathway that is essential for kidney development and commonly disrupted in WT. We propose a model in which the Wnt pathway can be disrupted in early kidney development to generate WT, either by genetic abnormalities such as WT1 mutations, or by epigenetic defects, such as ESRP2 methylation.

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“…Establishing the network between OS-related AS events and tumor-specific SFs, this research found that ESRP1 was associated with several OS-AS events that were correlated with OS. Similarly, ESRP1 was considered avital SF that leads to the progression and metastasis in pancreatic and prostate cancer [53,54]. While in addition to its role in splicing, PTBP1 also participates in the regulation of other aspects of RNA metabolism.…”

Section: Discussionmentioning

confidence: 99%

Systematic profiling of alternative splicing in Helicobacter pylori-negative gastric cancer and their clinical significance

Liu

et al. 2020

Cancer Cell Int

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Background: Alternative splicing (AS) may cause structural and functional variations in the protein to promote the proliferation of tumor cells. However, there is no comprehensive analysis of the clinical significance of AS in Helicobacter pylori-negative gastric cancer (HP − GC). Methods: The clinical, gene expression profile data and AS events of 138 HP − GC patients were obtained from the database named the cancer genome atlas. Differently expressed AS (DEAS) events were determined by a comparison of the PSI values between HP − GC samples and adjacent normal samples. Unsupervised clustering analysis, proportional regression and Kaplan-Meier analysis were used to explore the association between clinical data and immune features and to establish two nomograms about the prognosis of HP − GC. Finally, splicing networks were constructed using Cytoscape. Results: A total of 48141 AS events and 1041 DEAS events were found in HP − GC. Various functions and pathways of DEAS events parent genes were enriched, such as cell-substrate junction, cell leading edge, focal adhension, and AMPK signaling. Seven overall survival (OS)-related and seven disease-free survival (DFS)-related AS events were used to construct the prognostic signatures. Based on the independent prognostic factors, two nomograms were established and showed excellent performance. Then, splicing regulatory networks among the correlations suggested that splicing factors were significantly associated with prognostic DEASs. Finally, the unsupervised clustering analysis revealed that DEAS-based clusters were associated with clinical characteristics, tumor microenvironment, tumor mutation burden, and immune features. Conclusion: Seven OS-related and seven DFS-related AS events have been found to be correlated with the prognosis of HP − GC and can be used as prognostic factors to establish an effective nomogram.

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Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer

Cited by 52 publications

References 80 publications

Androgen receptor signaling regulates the transcriptome of prostate cancer cells by modulating global alternative splicing

Androgen receptor signaling regulates the transcriptome of prostate cancer cells by modulating global alternative splicing

The epithelial splicing regulatorESRP2is epigenetically repressed by DNA hypermethylation in Wilms tumour and acts as a tumour suppressor

Systematic profiling of alternative splicing in Helicobacter pylori-negative gastric cancer and their clinical significance

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