ATXN3 deubiquitinates YAP1 to promote tumor growth.
ATXN3 deubiquitinates YAP1 to promote tumor growth.
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DOI：
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发表时间：
2023
影响因子：
5.3
通讯作者：
Shengnan Wang;Kun Liu;Xiaohua Han;Yang Cheng;Emily Zhao;D. Brat;Zhaolin Sun;Deyu Fang
中科院分区：
文献类型：
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作者：
Shengnan Wang;Kun Liu;Xiaohua Han;Yang Cheng;Emily Zhao;D. Brat;Zhaolin Sun;Deyu Fang
泛素特异性多肽酶Aaxin-3(ATXN3)在多种人类癌症中具有潜在的致癌作用。然而，ATXN3如何实现其致瘤功能的分子机制在很大程度上仍不清楚。在此，我们报道了CRISPR-Cas9系统靶向缺失癌细胞中的ATXN3基因导致YAP1蛋白表达减少，而不改变其mRNA转录。有趣的是，ATXN3基因的抑制选择性地抑制了YAP1靶基因的表达水平，包括结缔组织生长因子(CTGF)和富含半胱氨酸的血管生成诱导物61(Cyr61)，这两个基因都在细胞黏附、迁移、增殖和血管生成中发挥重要作用。因此，ATXN3抑制导致癌细胞生长和迁移减少，这在很大程度上也可以通过YAP1重组来挽救。在分子水平上，ATNX3与YAP1的WW结构域相互作用，保护YAP1免受泛素化介导的降解。免疫组织化学分析显示，ATXN3和YAP1蛋白在人乳腺癌和胰腺癌中的表达呈显著正相关。总而言之，我们的研究将ATXN3定义为以前未知的YAP1脱泛素酶在肿瘤发生中的作用，并为ATXN3靶向抗肿瘤化疗提供了理论基础。
The ubiquitin-specific peptidase Ataxin-3 (ATXN3) has emerged as a potential oncogene in a variety of human cancers. However, the molecular mechanisms underlying how ATXN3 achieves its tumorigenic functions remain largely undefined. Herein, we report that targeted deletion of the ATXN3 gene in cancer cells by the CRISPR-Cas9 system resulted in decreased protein expression of Yes-associated protein 1 (YAP1) without altering its mRNA transcription. Interestingly, genetic ATXN3 suppression selectively inhibited the expression levels of YAP1 target genes including the connective tissue growth factor (Ctgf) and cysteine-rich angiogenic inducer 61 (Cyr61), both of which have important functions in cell adhesion, migration, proliferation and angiogenesis. Consequently, ATXN3 suppression resulted in reduced cancer cell growth and migration, which can also be largely rescued by YAP1 reconstitution. At the molecular level, ATNX3 interacts with the WW domains of YAP1 to protect YAP1 from ubiquitination-mediated degradation. Immunohistology analysis revealed a strong positive correlation between ATXN3 and YAP1 protein expression in human breast and pancreatic cancers. Collectively, our study defines ATXN3 as a previously unknown YAP1 deubiquitinase in tumorigenesis and provides a rationale for ATXN3 targeting in antitumor chemotherapy.