USP44失活加速甲状腺癌的进展：诱导p21的泛素化与降解
USP44 inactivation accelerates the progression of thyroid cancer by inducing ubiquitylation and degradation of p21
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影响因子:10
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
DOI:
10.7150/ijbs.99817
摘要
泛素特异性蛋白酶44（USP44）属于泛素特异性蛋白酶家族，在多种人类癌症的肿瘤发生和进展中起关键作用。然而，其在甲状腺癌中的生物学功能及机制尚不清楚。在本研究中，我们观察到USP44在甲状腺癌中经常通过启动子高甲基化被下调，且其表达降低与患者预后不良密切相关。体外和体内的功能研究表明，USP44通过阻碍细胞周期中的G1/S转变，显著抑制甲状腺癌细胞的增殖。机制上，USP44直接与p21相互作用，去除其K-48链的多泛素化，从而在细胞周期无关的情况下稳定p21蛋白。此外，p21的“救援”部分缓解了USP44耗竭引起的细胞周期加快和细胞增殖。综上所述，USP44在甲状腺癌中由于启动子高甲基化而常被沉默，其作为肿瘤抑制基因通过去泛素化稳定p21发挥抑癌作用。
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.