E3泛素连接酶的失调会驱动各种癌症的增殖和转移；然而，其根本机制仍然未知。本研究旨在探讨含有三联基序的 22 (TRIM22)（TRIM 家族中一种尚未充分研究的 E3 泛素连接酶）作为乳腺癌肿瘤抑制因子的作用。 TRIM22 在乳腺癌中的高表达与更好的预后相关。功能实验表明TRIM22显着抑制乳腺癌细胞的增殖和侵袭。无标记蛋白质组学和生化分析表明，超氧化物歧化酶 (CCS) 的铜伴侣是 TRIM22 通过 K27 连接的泛素化降解的目标，超氧化物歧化酶是一种在乳腺癌中上调并促进乳腺癌细胞生长和侵袭的癌蛋白。 。值得注意的是，TRIM22 卷曲螺旋结构域缺陷突变体诱导 CCS 泛素化和降解的能力减弱，CCS 的赖氨酸 76 作为泛素化位点。此外，异位CCS表达恢复了TRIM22介导的对乳腺癌细胞增殖和侵袭的抑制。使用基因集富集分析的 RNA 测序实验表明 TRIM22 参与 JAK-STAT 信号通路。 TRIM22 过表达还提高了乳腺癌细胞中的活性氧水平，并抑制 STAT3 磷酸化，而 STAT3 磷酸化可通过 CCS 过表达或 N-乙酰基-L-半胱氨酸治疗恢复。染色质免疫沉淀-定量聚合酶链反应结果显示，TRIM22 过表达降低了 FN1、VIM 和 JARID2 启动子中磷酸化 STAT3 的富集。临床上，低 TRIM22 表达与高 CCS 表达相关，并降低乳腺癌患者的生存率。此外，TRIM22 上调与接受经典治疗的乳腺癌患者更好的预后相关。 TRIM22 表达在许多癌症类型中下调，包括结肠癌、肾癌、肺癌和前列腺癌。据我们所知，E3泛素连接酶TRIM22首次被报道为一种肿瘤抑制因子，通过CCS泛素化和降解来抑制乳腺癌细胞的增殖和侵袭。 TRIM22 是乳腺癌患者的潜在预后生物标志物。版权所有 © 2024。由 Elsevier B.V. 出版。

Deregulation of E3 ubiquitin ligases drives the proliferation and metastasis of various cancers; however, the underlying mechanisms remain unknown. This study aimed to investigate the role of tripartite motif-containing 22 (TRIM22), a poorly investigated E3 ubiquitin ligase in the TRIM family, as a tumor suppressor in breast cancer. High expression of TRIM22 in breast cancer correlated with better prognosis. Functional experiments demonstrated that TRIM22 significantly inhibited the proliferation and invasion of breast cancer cells. Label-free proteomics and biochemical analyses revealed that the copper chaperone for superoxide dismutase (CCS), an oncoprotein that is upregulated in breast cancer and promotes the growth and invasion of breast cancer cells, was a target of TRIM22 for degradation via K27-linked ubiquitination. Notably, the ability of the coiled-coil domain-defective mutants of TRIM22 to induce CCS ubiquitination and degradation diminished, with lysine 76 of the CCS serving as the ubiquitination site. Moreover, the TRIM22-mediated inhibition of the proliferation and invasion of breast cancer cells was restored by ectopic CCS expression. RNA-sequencing experiments using Gene Set Enrichment Analysis demonstrated that TRIM22 is involved in the JAK-STAT signaling pathway. TRIM22 overexpression also improved reactive oxygen species levels in breast cancer cells and inhibited STAT3 phosphorylation, which was restored via CCS overexpression or N-acetyl-L-cysteine treatment. Chromatin immunoprecipitation-quantitative polymerase chain reaction results showed that TRIM22 overexpression decreased the enrichment of phosphorylated STAT3 in FN1, VIM and JARID2 promoters. Clinically, low TRIM22 expression correlated with high CCS expression and decreased survival rates in patients with breast cancer. Moreover, TRIM22 upregulation was associated with a better prognosis in patients with breast cancer who received classical therapy. TRIM22 expression was downregulated in many cancer types, including colon, kidney, lung, and prostate cancers. To the best of our knowledge, the E3 ubiquitin ligase TRIM22 was first reported as a tumor suppressor that inhibits the proliferation and invasion of breast cancer cells through CCS ubiquitination and degradation. TRIM22 is a potential prognostic biomarker in patients with breast cancer.Copyright © 2024. Published by Elsevier B.V.