The E3 ubiquitin ligase TRIM7 suppressed hepatocellular carcinoma progression by directly targeting Src protein.,Cell Death and Differentiation

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The E3 ubiquitin ligase TRIM7 suppressed hepatocellular carcinoma progression by directly targeting Src protein.
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2019-12-04 , DOI: 10.1038/s41418-019-0464-9
Lihui Zhu _{1,

2,

3} , Chengyong Qin _{2,

3} , Tao Li ₄ , Xiaomin Ma ₁ , Yumin Qiu ₁ , Yueke Lin ₁ , Dapeng Ma ₁ , Zhenzhi Qin ₁ , Caiyu Sun ₁ , Xuecheng Shen ₁ , Yunxue Zhao ₅ , Lihui Han ₁

Affiliation

Aberrant Src kinase activity is known to be involved in a variety of human malignancies, whereas the regulatory mechanism of Src has not been completely clarified. Here, we demonstrated that tripartite motif containing 7 (TRIM7) directly interacted with Src, induced Lys48-linked polyubiquitination of Src and reduced the abundance of Src protein in hepatocellular carcinoma (HCC) cells. We further identified TRIM7 as a tumor suppressor in HCC cells through its negative modulation of the Src-mTORC1-S6K1 axis in vivo and in vitro in several HCC models. Moreover, we verified the dysregulated expression of TRIM7 in clinical liver cancer tissues and its negative correlation with Src protein in clinical HCC specimens. Overall, we demonstrated that TRIM7 suppressed HCC progression through its direct negative regulation of Src and modulation of the Src-mTORC1-S6K1 axis; thus, we provided a novel insight into the development of HCC and defined a promising therapeutic strategy for cancers with overactive Src by modulating TRIM7.

中文翻译：

E3 泛素连接酶 TRIM7 通过直接靶向 Src 蛋白抑制肝细胞癌进展。

已知异常的 Src 激酶活性与多种人类恶性肿瘤有关，而 Src 的调节机制尚未完全阐明。在这里，我们证明了包含 7 (TRIM7) 的三方基序直接与 Src 相互作用，诱导 Lys48 连接的 Src 多泛素化并降低肝细胞癌 (HCC) 细胞中 Src 蛋白的丰度。我们通过在几种 HCC 模型中体内和体外对 Src-mTORC1-S6K1 轴的负调节，进一步将 TRIM7 鉴定为 HCC 细胞中的肿瘤抑制因子。此外，我们验证了临床肝癌组织中TRIM7的表达失调及其与临床HCC标本中Src蛋白的负相关。总体，我们证明了 TRIM7 通过其对 Src 的直接负调节和 Src-mTORC1-S6K1 轴的调节抑制了 HCC 进展；因此，我们提供了对 HCC 发展的新见解，并通过调节 TRIM7 为 Src 过度活跃的癌症定义了一种有前途的治疗策略。

更新日期：2019-12-04

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