USP44通过诱导P21的泛素化和降解来加速甲状腺癌的进展
USP44 inactivation accelerates the progression of thyroid cancer by inducing ubiquitylation and degradation of p21
影响因子:10.00000
分区:生物学1区 Top / 生化与分子生物学2区
发表日期:2024
作者:
Yan Liu, Mengmeng Yuan, Xinxin Xu, Huini Yang, Yao Yao, Peng Hou, Wei Yu, Meiju Ji
摘要
泛素特异性肽酶44（USP44）属于泛素特异性蛋白酶家族，在各种人类癌症的肿瘤的发展和发展中都是关键的。然而，其生物学功能和甲状腺癌的潜在机制知之甚少。在这项研究中，我们观察到USP44经常被甲状腺癌中的启动子高甲基化下调，发现其表达降低与患者生存率差密切相关。随后的体外和体内功能研究表明，USP44通过阻碍细胞周期中的G1/S转变来实质性地抑制甲状腺癌细胞的增殖。从机械上讲，USP44与P21直接相互作用并消除了其K-48连接的多泛素化链，从而以与细胞周期无关的方式稳定P21蛋白。此外，p21的救助部分减轻了USP44耗竭引起的细胞周期进步和细胞增殖。我们的发现共同表明，由于启动子高甲基化和通过去泛素化稳定P21的作用，USP44经常在甲状腺癌中受到抑制。
Abstract
Ubiquitin-specific peptidase 44 (USP44) belongs to the ubiquitin-specific protease family and is pivotal in the development and progression of tumors across various human cancers. However, its biological function and the underlying mechanisms in thyroid cancer remain poorly understood. In this study, we observed that USP44 was frequently downregulated by promoter hypermethylation in thyroid cancers and found that its decreased expression was closely associated with poor patient survival. Subsequent in vitro and in vivo functional studies revealed that USP44 substantially suppressed the proliferation of thyroid cancer cells by impeding the G1/S transition in cell cycle. Mechanistically, USP44 directly interacted with p21 and eliminated its K-48-linked polyubiquitination chain, thereby stabilizing p21 proteins in a cell cycle-independent manner. In addition, the rescue of p21 partially alleviated cell cycle advancement and cell proliferation induced by the depletion of USP44. Our findings, taken together, indicate that USP44 is frequently repressed in thyroid cancer due to promoter hypermethylation and functions as a tumor suppressor by stabilizing p21 via deubiquitination.