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USP44 失活通过诱导 p21 的泛素化和降解加速甲状腺癌的进展。

USP44 inactivation accelerates the progression of thyroid cancer by inducing ubiquitylation and degradation of p21.

机构信息

International Joint Research Center for Tumor Precision Medicine of Shaanxi Province and Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China.

BioBank, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China.

出版信息

Int J Biol Sci. 2024 Sep 23;20(13):5223-5238. doi: 10.7150/ijbs.99817. eCollection 2024.

DOI:10.7150/ijbs.99817
PMID:39430240
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11489182/
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 was frequently downregulated by promoter hypermethylation in thyroid cancers and found that its decreased expression was closely associated with poor patient survival. Subsequent and 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.

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发生和进展中起着关键作用。然而，其在甲状腺癌中的生物学功能和潜在机制仍知之甚少。在这项研究中，我们观察到 USP44 在甲状腺癌中常因启动子过度甲基化而被下调，并且发现其表达水平的降低与患者预后不良密切相关。随后的 USP44 功能研究表明，USP44 通过抑制细胞周期中的 G1/S 转换，显著抑制甲状腺癌细胞的增殖。其机制为，USP44 可直接与 p21 相互作用，并消除其 K-48 连接的多泛素化链，从而以细胞周期非依赖性的方式稳定 p21 蛋白。此外，通过耗尽 USP44 诱导的细胞周期进展和细胞增殖可被 p21 的挽救部分缓解。综上，我们的研究结果表明，USP44 因启动子过度甲基化而在甲状腺癌中常被抑制，并通过去泛素化稳定 p21 发挥抑癌作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac8f/11489182/c515480279d5/ijbsv20p5223g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac8f/11489182/c515480279d5/ijbsv20p5223g008.jpg

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The deubiquitinating enzyme USP44 suppresses hepatocellular carcinoma progression by inhibiting Hedgehog signaling and PDL1 expression.去泛素化酶 USP44 通过抑制 Hedgehog 信号通路和 PDL1 表达抑制肝癌进展。
Cell Death Dis. 2023 Dec 14;14(12):830. doi: 10.1038/s41419-023-06358-y.
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Genomic alterations in thyroid cancer: biological and clinical insights.
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Cancer statistics, 2023.癌症统计数据，2023 年。
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