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
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U2 相关蛋白 CHERP 和 SR140 通过选择性剪接调节促进结直肠肿瘤发生
DOI：
10.1002/ijc.32331
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发表时间：
2019-11-15
影响因子：
6.4
通讯作者：
Feng, Ying
中科院分区：
文献类型：
--
作者：
Wang, Qianqian;Wang, Yue;Feng, Ying
钙稳态内质网蛋白（CHERP）的失调已涉及几种癌症，但它仍然是难以捉摸的CHERP如何有助于癌细胞增殖和癌症的发展。在这里，我们观察到CHERP及其结合伴侣SR 140在人类临床结直肠癌组织（CRC）中显著上调。CHERP和SR 140可以形成蛋白质复合物以相互稳定。CHERP或SR 140的敲低触发双链DNA断裂和细胞死亡。此外，RNA监视因子UPF 3A被鉴定为CHERP和SR 140的剪接靶点，其特异性结合于受调控的外显子4并调节UPF 3A剪接。UPF 3A敲除在体外和小鼠中再现CHERP/SR 140消耗。重要的是，UPF 3A的过表达显著挽救CHERP/SR 140耗尽细胞的增殖缺陷。这些结果证实了CHERP/SR 140促进肿瘤发生的作用部分由UPF 3A介导。扩展这些结果，在CRC中观察到的CHERP/SR 140的上调显著地平行于UPF 3A外显子4的增加。总之，我们的研究阐明了CHERP/SR 140如何部分通过调节UPF 3A变体的表达在CRC发展中发挥致癌作用。
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.