OTUB1 facilitates bladder cancer progression by stabilizing ATF6 in response to endoplasmic reticulum stress.
OTUB1 facilitates bladder cancer progression by stabilizing ATF6 in response to endoplasmic reticulum stress.
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OTUB1 通过稳定 ATF6 响应内质网应激促进膀胱癌进展
DOI：
10.1111/cas.14876
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发表时间：
2021-06
期刊：
影响因子：
5.7
通讯作者：
Li SZ
中科院分区：
文献类型：
--
作者：
Zhang HH;Li C;Ren JW;Liu L;Du XH;Gao J;Liu T;Li SZ
未折叠蛋白反应（UPR）在膀胱癌发生中起重要作用，但UPR相关膀胱癌发生的功能作用和机制仍有待进一步研究。在UPR激活后，ATF6α被激活以上调UPR靶基因的转录。虽然ATF6激活的机制已被广泛研究，但对ATF6稳定的负调控还没有很好的理解。在这里，我们报告说，去泛素化酶otubain 1（OTUB 1）促进膀胱癌的进展，稳定ATF6在内质网应激。OTUB 1表达在膀胱癌患者中升高。OTUB 1的基因消融在体外和体内均显著抑制膀胱癌细胞增殖、活力和迁移。从机制上讲，荧光素酶途径筛选显示，与其他途径相比，ATF6信号传导明显被激活。OTUB 1通过抑制ATF6的泛素化而激活ATF6信号，从而通过转录调控重塑应激细胞。我们的研究结果表明，OTUB 1高表达通过稳定ATF 6促进膀胱癌进展，OTUB 1是膀胱癌的潜在治疗靶点。我们的研究结果表明，OTUB 1高表达通过稳定ATF 6促进膀胱癌进展，OTUB 1是膀胱癌的潜在治疗靶点。
The unfolded protein response (UPR) plays an important role in carcinogenesis, but the functional role and mechanism of UPR‐associated bladder carcinogenesis remain to be characterized. Upon UPR activation, ATF6α is activated to upregulate the transcription of UPR target genes. Although the mechanism of ATF6 activation has been studied extensively, the negative regulation of ATF6 stabilization is not well understood. Here, we report that the deubiquitinase otubain 1 (OTUB1) facilitates bladder cancer progression by stabilizing ATF6 in response to endoplasmic reticulum stress. OTUB1 expression is raised in bladder cancer patients. Genetic ablation of OTUB1 markedly inhibited bladder cancer cell proliferation, viability, and migration both in vitro and in vivo. Mechanistically, luciferase pathway screening showed that ATF6 signaling was clearly activated compared with other pathways. OTUB1 was found to activate ATF6 signaling by inhibiting its ubiquitylation, thereby remodeling the stressed cells through transcriptional regulation. Our results show that high OTUB1 expression promotes bladder cancer progression by stabilizing ATF6 and that OTUB1 is a potential therapeutic target in bladder cancer. Our results show that high OTUB1 expression promotes bladder cancer progression by stabilizing ATF6 and that OTUB1 is a potential therapeutic target in bladder cancer.
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影响因子：
6.3
作者：
Hanaoka M;Ishikawa T;Ishiguro M;Tokura M;Yamauchi S;Kikuchi A;Uetake H;Yasuno M;Kawano T
通讯作者：
Kawano T
影响因子：
11.8
作者：
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通讯作者：
Flores-Morales A
影响因子：
6.2
作者：
Charlton, Mary E.;Adamo, Margaret (Peggy);Sun, Leon;Deorah, Sundeep
通讯作者：
Deorah, Sundeep