SRSF6-regulated alternative splicing that promotes tumour progression offers a therapy target for colorectal cancer

Wan, Ledong; Yu, Wenying; Shen, Enhui; Sun, Wenjie; Liu, Yuan; Kong, Jie; Wu, Yihua; Han, Fengyan; Zhang, Lei; Yu, Tianze; Zhou, Yuwei; Xie, Sun‐Zhe; Xu, Enbo; Zhang, Honghe; Lai, Maode

doi:10.1136/gutjnl-2017-314983

Cited by 138 publications

(154 citation statements)

References 31 publications

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“…Levels of splicing factors such as SRSF1, SRSF6, SRSF10, hnRNPK or hnRNPLL are significantly altered in many types of cancer including CRC . Therefore, it is not surprising that dysregulated AS events can contribute to almost all hallmarks of cancer, including sustained proliferation and evasion of apoptosis .…”

Section: Discussionmentioning

confidence: 99%

U2‐related proteins CHERP and SR140 contribute to colorectal tumorigenesis via alternative splicing regulation

Wang

Liu

et al. 2019

Intl Journal of Cancer

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Dysregulation of calcium homeostasis endoplasmic reticulum protein (CHERP) has been implicated in several cancers, but it remains elusive how CHERP contributes to cancer cell proliferation and cancer development. Here, we observed that CHERP and its binding partner SR140 are significantly upregulated in human clinical colorectal cancer tissues (CRC). CHERP and SR140 could form a protein complex to stabilize each other. Knockdown of CHERP or SR140 triggers double‐stranded DNA breaks and cell death. Furthermore, UPF3A, the RNA surveillance factor, was identified as a splicing target of CHERP and SR140, which bind specifically to the regulated exon4 and modulate UPF3A splicing. UPF3A knockdown recapitulates CHERP/SR140 depletion both in vitro and in mice. Importantly, overexpression of UPF3A significantly rescues proliferation defect of CHERP/SR140‐depleted cells. These results confirmed that the effect of CHERP/SR140 in promoting tumorigenesis was partially mediated by UPF3A. Extending these results, upregulation of CHERP/SR140 observed in CRC remarkably parallels increased inclusion of UPF3A exon4. Together, our study clarifies how CHERP/SR140 exert an oncogenic role in CRC development partially through regulating expression of UPF3A variants.

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Section: Discussionmentioning

confidence: 99%

U2‐related proteins CHERP and SR140 contribute to colorectal tumorigenesis via alternative splicing regulation

Wang

Liu

et al. 2019

Intl Journal of Cancer

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“…Aberrant expression of SR proteins is present in multiple types of cancer, including leukaemia, kidney, breast, colon, pancreas and lung cancers, among others . SRp55 has been implicated in the development of skin and colorectal cancer . SRp55 is classified as a proto‐oncogene, since its overexpression results in hyperplasia, increased cell proliferation and motility …”

Section: Srsf6 (Srp55): a Major Splicing Regulatory Protein In β‐Cellsmentioning

confidence: 99%

“…SRp55 has been implicated in the development of skin and colorectal cancer . SRp55 is classified as a proto‐oncogene, since its overexpression results in hyperplasia, increased cell proliferation and motility …”

Section: Srsf6 (Srp55): a Major Splicing Regulatory Protein In β‐Cellsmentioning

confidence: 99%

“…91 SRp55 has been implicated in the development of skin and colorectal cancer. 92,93 SRp55 is classified as a proto-oncogene, since its overexpression results in hyperplasia, increased cell proliferation and motility. 92,93 In β-cells, SRp55 gene expression is under regulation of the T1D and T2D susceptibility gene GLIS3, and its expression is decreased by pro-inflammatory cytokines.…”

Section: Alternative Splicing Autoimmunity and The Triggering Of T1dmentioning

confidence: 99%

“…92,93 SRp55 is classified as a proto-oncogene, since its overexpression results in hyperplasia, increased cell proliferation and motility. 92,93 In β-cells, SRp55 gene expression is under regulation of the T1D and T2D susceptibility gene GLIS3, and its expression is decreased by pro-inflammatory cytokines. 11,13 RNA sequencing analysis of The decrease in functional β-cell mass, mostly resulting from apoptosis, is a determining factor for T1D development.…”

Section: Alternative Splicing Autoimmunity and The Triggering Of T1dmentioning

confidence: 99%

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When one becomes many—Alternative splicing in β‐cell function and failure

Alvelos

Juan-Mateu

Colli

et al. 2018

Diabetes Obesity Metabolism

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Pancreatic β-cell dysfunction and death are determinant events in type 1 diabetes (T1D), but the molecular mechanisms behind β-cell fate remain poorly understood. Alternative splicing is a post-translational mechanism by which a single gene generates different mRNA and protein isoforms, expanding the transcriptome complexity and enhancing protein diversity. Neuron-specific and certain serine/arginine-rich RNA binding proteins (RBP) are enriched in β-cells, playing crucial roles in the regulation of insulin secretion and β-cell survival. Moreover, alternative exon networks, regulated by inflammation or diabetes susceptibility genes, control key pathways and processes for the correct function and survival of β-cells. The challenge ahead of us is to understand the precise role of alternative splicing regulators and splice variants on β-cell function, dysfunction and death and develop tools to modulate it.

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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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SRSF6-regulated alternative splicing that promotes tumour progression offers a therapy target for colorectal cancer

Abstract: The accession numbers for sequencing data are SRP111763 and SRP111797.

Cited by 138 publications

References 31 publications

U2‐related proteins CHERP and SR140 contribute to colorectal tumorigenesis via alternative splicing regulation

U2‐related proteins CHERP and SR140 contribute to colorectal tumorigenesis via alternative splicing regulation

When one becomes many—Alternative splicing in β‐cell function and failure

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

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