Androgen-regulated transcription of<i>ESRP2</i>drives alternative splicing patterns in prostate cancer

Munkley, Jennifer; Li, Ling; Krishnan, Subha; Hysenaj, Gerald; Scott, Emma; 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:10.1101/629618

Cited by 2 publications

(4 citation statements)

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“…The splicing factor is responsible for the splicing process. Alternative splicing induced by abnormal expression and/or mutations of splicing factors is an important molecular feature of tumorigenesis [12][13][14][15]. The abnormal expression of splicing factors can induce changes in many key tumor-related genes, such as RON, BIN1, S6K1, MNK2, BIM, and BCL-x, which in turn affects malignant phenotypes including cell proliferation, metastasis, chemoresistance, and other processes [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

SF3B1 mutation in pancreatic cancer contributes to aerobic glycolysis and tumor growth through a PP2A–c‐Myc axis

et al. 2021

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Hot spot gene mutations in splicing factor 3b subunit 1 (SF3B1) are observed in many types of cancer and create abundant aberrant mRNA splicing, which is profoundly implicated in tumorigenesis. Here, we identified that the SF3B1 K700E (SF3B1K700E) mutation is strongly associated with tumor growth in pancreatic ductal adenocarcinoma (PDAC). Knockdown of SF3B1 significantly retarded cell proliferation and tumor growth in a cell line (Panc05.04) with the SF3B1K700E mutation. However, SF3B1 knockdown had no notable effect on cell proliferation in two cell lines (BxPC3 and AsPC1) carrying wild‐type SF3B1. Ectopic expression of SF3B1K700E but not SF3B1WT in SF3B1‐knockout Panc05.04 cells largely restored the inhibitory role induced by SF3B1 knockdown. Introduction of the SF3B1K700E mutation in BxPC3 and AsPC1 cells also boosted cell proliferation. Gene set enrichment analysis demonstrated a close correlation between SF3B1 mutation and aerobic glycolysis. Functional analyses showed that the SF3B1K700E mutation promoted tumor glycolysis, as evidenced by glucose consumption, lactate release, and extracellular acidification rate. Mechanistically, the SF3B1 mutation promoted the aberrant splicing of PPP2R5A and led to the activation of the glycolytic regulator c‐Myc via post‐translational regulation. Pharmacological activation of PP2A with FTY‐720 markedly compromised the growth advantage induced by the SF3B1K700E mutation in vitro and in vivo. Taken together, our data suggest a novel function for SF3B1 mutation in the Warburg effect, and this finding may offer a potential therapeutic strategy against PDAC with the SF3B1K700E mutation.

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Section: Introductionmentioning

confidence: 99%

SF3B1 mutation in pancreatic cancer contributes to aerobic glycolysis and tumor growth through a PP2A–c‐Myc axis

et al. 2021

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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: 85%

“…Splicing alterations are frequent in human cancers (69), including changes induced by ESRP genes, such as in breast cancer (54, 70), prostate cancer (68, 71), renal cell carcinoma (72) and colorectal cancer (73). In most cases, ESRP genes appear to have tumour suppressive properties, presumably because loss of ESRP expression permits EMT (27, 39), which is important in many stages of carcinogenesis, especially the acquisition of malignant characteristics i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Most studies on ESRP genes in human cancer demonstrate expression changes but without any reported underlying genetic or epigenetic defects in the ESRP genes themselves (54, 68, 70, 72, 73). However, there have been reports of genetic defects in ESRP genes in human cancers, specifically, microsatellite indels (75) or duplications (71) of ESRP1 .…”

Section: Discussionmentioning

confidence: 99%

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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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Androgen-regulated transcription ofESRP2drives alternative splicing patterns in prostate cancer

Cited by 2 publications

References 74 publications

SF3B1 mutation in pancreatic cancer contributes to aerobic glycolysis and tumor growth through a PP2A–c‐Myc axis

SF3B1 mutation in pancreatic cancer contributes to aerobic glycolysis and tumor growth through a PP2A–c‐Myc axis

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

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