Abstract
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.
Highlights
Breast cancer is the most commonly diagnosed cancer among women worldwide, and the latest global cancer burden data released by the World Health Organization in 2020 show that the global number of new cases of breast cancer is as high as 2.26 million, surpassing lung cancer to become the world’s most common cancer; it ranks among the top five cancers worldwide in terms of mortality rate
In this study, we verified that Tripartite motif-containing 31 (TRIM31) expression was downregulated in breast cancer and that low TRIM31 levels were associated with worse survival outcomes than high levels in breast cancer patients
All these data suggest that TRIM31 acts as a tumor suppressor in breast cancer and may be a valuable prognostic biomarker in breast cancer patients
Summary
Breast cancer is the most commonly diagnosed cancer among women worldwide, and the latest global cancer burden data released by the World Health Organization in 2020 show that the global number of new cases of breast cancer is as high as 2.26 million, surpassing lung cancer to become the world’s most common cancer; it ranks among the top five cancers worldwide in terms of mortality rate. The E3 ligase RING1 promotes cancer cell proliferation and survival by targeting p53 for ubiquitination and degradation [14]. All these results indicate that P53 ubiquitination plays an important role in the occurrence and development of tumors. The role and mechanism of TRIM31 inhibited the migration and invasion of breast cancer cells in breast cancer progression are still not clear. TRIM31 directly TRIM31 directly binds to the p53 protein interacted with p53 and subsequently stabilized and activated p53 To elucidate the molecular mechanism of TRIM31-mediated antiby inducing K63-linked ubiquitination as well as inhibiting MDM2- tumor function in breast cancer, we used proteomics and mediated K48-linked ubiquitination of p53.
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