Chemotherapeutic agents for treating colorectal cancer (CRC) primarily induce apoptosis in tumor cells. The ubiquitin-proteasome system is critical for apoptosis regulation. Deubiquitinating enzymes (DUBs) remove ubiquitin from substrates to reverse ubiquitination. Although over 100 DUB members have been discovered, the biological functions of only a small proportion of DUBs have been characterized. Here, we aimed to systematically identify the DUBs that contribute to the development of CRC. Among the DUBs, ubiquitin-specific protease 36 (USP36) is upregulated in CRC. We showed that the knockdown of induces intrinsic and extrinsic apoptosis. Through gene silencing and coimmunoprecipitation techniques, we identified survivin and cIAP1 as USP36 targets. Mechanistically, USP36 binds and removes lysine-11–linked ubiquitin chains from cIAP1 and lysine-48–linked ubiquitin chains from survivin to abolish protein degradation. Overexpression of disrupts the formation of the XIAP–second mitochondria-derived activator of caspase complex and promotes receptor-interacting protein kinase 1 ubiquitination, validating USP36 as an inhibitor to intrinsic and extrinsic apoptosis through deubiquitinating survivin and cIAP1. Therefore, our results suggest that USP36 is involved in CRC progression and is a potential therapeutic target.

中文翻译：

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USP36 通过去泛素化结直肠癌细胞中的 cIAP1 和 survivin 抑制细胞凋亡


用于治疗结直肠癌（CRC）的化疗药物主要诱导肿瘤细胞凋亡。泛素-蛋白酶体系统对于细胞凋亡调节至关重要。去泛素化酶 (DUB) 可从底物中去除泛素，从而逆转泛素化。尽管已经发现了 100 多个 DUB 成员，但只有一小部分 DUB 的生物学功能得到了表征。在这里，我们的目标是系统地识别有助于 CRC 发展的 DUB。在 DUB 中，泛素特异性蛋白酶 36 (USP36) 在 CRC 中表达上调。我们发现 的敲低会诱导内在和外在的细胞凋亡。通过基因沉默和免疫共沉淀技术，我们确定了 survivin 和 cIAP1 作为 USP36 的靶点。从机制上讲，USP36 结合并去除 cIAP1 中的赖氨酸 11 连接的泛素链和生存素中的赖氨酸 48 连接的泛素链，从而消除蛋白质降解。的过度表达会破坏 XIAP（第二个线粒体衍生的 caspase 复合物激活剂）的形成，并促进受体相互作用蛋白激酶 1 泛素化，从而验证 USP36 通过使 survivin 和 cIAP1 去泛素化作为内在和外在细胞凋亡的抑制剂。因此，我们的结果表明USP36参与CRC进展并且是潜在的治疗靶点。