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U2‐related proteins CHERP and SR140 contribute to colorectal tumorigenesis via alternative splicing regulation
Author(s) -
Wang Qianqian,
Wang Yue,
Liu Yuguo,
Zhang Chang,
Luo Yangjun,
Guo Ruochen,
Zhan Zheng,
Wei Ning,
Xie Zhiqin,
Shen Lei,
Wu Guohao,
Wu Wenwu,
Feng Ying
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32331
Subject(s) - gene knockdown , carcinogenesis , downregulation and upregulation , biology , rna splicing , endoplasmic reticulum , alternative splicing , microbiology and biotechnology , cell growth , cancer research , unfolded protein response , splicing factor , rna binding protein , cancer , rna , genetics , cell culture , messenger rna , gene
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.