U2‐related proteins CHERP and SR140 contribute to colorectal tumorigenesis via alternative splicing regulation. Issue 10 (25th April 2019)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: International journal of cancer. Volume 145:Issue 10(2019)
• Page Start: 2728
• Page End: 2739
• Publication Date: 2019-04-25
• Subjects: alternative splicing -- U2‐related splicing factors -- cancer cell proliferation -- apoptosis -- cancer development -- double‐stranded DNA breaks -- splicing regulation; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32331
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : 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. Abstract : What's new? Alternative splicing is a highly complicated process that not only regulates gene expression but also increases protein diversity. Dysregulation of CHERP—a protein belonging to the spliceosome and related to the core component U2—has been implicated in several cancers, but it remains elusive how CHERP contributes to cancer cell proliferation and cancer development. This study provides substantial insight into the biological significance of CHERP and its binding partner SR140 in colorectal tumorigenesis and identifies the RNA surveillance factor UPF3A as their key splicing target for mediating and maintaining oncogenic phenotypes of human colon cancer cells.