Loss of TRIM31 promotes breast cancer progression through regulating K48- and K63-linked ubiquitination of p53.
Loss of TRIM31 promotes breast cancer progression through regulating K48- and K63-linked ubiquitination of p53.
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TRIM31 缺失通过调节 p53 的 K48 和 K63 泛素化促进乳腺癌进展
DOI：
10.1038/s41419-021-04208-3
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发表时间：
2021-10-14
影响因子：
9
通讯作者：
Lin P
中科院分区：
文献类型：
--
作者：
Guo Y;Li Q;Zhao G;Zhang J;Yuan H;Feng T;Ou D;Gu R;Li S;Li K;Lin P
乳腺癌是世界上最常见的癌症。复发和转移是危及乳腺癌患者生命的重要因素，但其发生机制尚不清楚。p53的稳定性对防止肿瘤的发生至关重要，而泛素化是调节p53稳定性的主要途径之一。TRIM31是TRIM家族的新成员，具有E3泛素连接酶的功能。它在多种癌症的恶性过程中充当癌症促进剂或抑制剂。然而，TRIM31在乳腺癌进展中的功能仍然未知。在这项研究中，我们发现TRIM31在乳腺癌组织中下调，并与乳腺癌进展呈负相关。功能获得和功能丧失测定均表明TRIM31抑制乳腺癌细胞的增殖、集落形成、迁移和侵袭。进一步的研究表明，TRIM31直接与p53相互作用，通过其RING结构域诱导p53的K63泛素化，同时通过竞争性抑制MDM 2与p53的相互作用，抑制MDM 2介导的K48泛素化，导致p53的稳定和激活。p53基因的敲除逆转了TRIM 31对乳腺癌细胞生长和转移的抑制作用。此外，我们发现TRIM 31的RING和卷曲螺旋（C-C）结构域对于其肿瘤抑制功能是必需的。总之，我们的研究结果揭示了TRIM31通过稳定和激活p53抑制乳腺癌发展的新机制，并确定了恢复TRIM31治疗乳腺癌的有前途的治疗策略。
Breast cancer is the most common cancer in the world. Relapse and metastasis are important factors endangering the life of breast cancer patients, but the mechanism is still unclear. The stabilization of p53 is essential for preventing carcinogenesis, and ubiquitination is one of the main ways to regulate the stability of p53. Tripartite motif-containing 31 (TRIM31) is a new member of the TRIM family and functions as an E3 ubiquitin ligase. It acts as a cancer promoter or suppressor in the malignant processes of multiple cancers. However, the function of TRIM31 in breast cancer progression remains unknown. In this study, we showed that TRIM31 is downregulated in breast cancer tissues and negatively correlated with breast cancer progression. Both gain- and loss-of-function assays indicated that TRIM31 inhibits the proliferation, colony formation, migration, and invasion of breast cancer cells. Further investigation demonstrated that TRIM31 directly interacts with p53, and inducing the K63-linked ubiquitination of p53 via its RING domain, Meanwhile, TRIM31 suppresses the MDM2-mediated K48-linked ubiquitination of p53 through competitive inhibiting the interaction of MDM2 and p53, leading to the p53 stabilization and activation. Knockdown of p53 reversed the inhibitory effects of TRIM31 on the growth and metastasis of breast cancer cells. Moreover, we found that the RING and coiled-coil (C–C) domains of TRIM31 were essential for its tumor suppressor function. Taken together, our findings reveal a novel mechanism by which TRIM31 suppresses breast cancer development through the stabilization and activation of p53 and define a promising therapeutic strategy for restoring TRIM31 to treat breast cancer.
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影响因子：
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作者：
Li, Hui;Zhang, Yi;He, Ping
通讯作者：
He, Ping
影响因子：
4.8
作者：
Tripathi, Vivek;Kaur, Ekjot;Sengupta, Sagar
通讯作者：
Sengupta, Sagar
影响因子：
12.4
作者：
Liu, Ju;Zhang, C.;Feng, Z.
通讯作者：
Feng, Z.
影响因子：
64.5
作者：
Kruse JP;Gu W
通讯作者：
Gu W
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影响因子：
3
作者：
Shi, G.;Lv, C.;Wang, D.
通讯作者：
Wang, D.