The E3 Ligase TRIM4 Facilitates SET Ubiquitin-Mediated Degradation to Enhance ER-α Action in Breast Cancer.
The E3 Ligase TRIM4 Facilitates SET Ubiquitin-Mediated Degradation to Enhance ER-α Action in Breast Cancer.
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E3 连接酶 TRIM4 促进 SET 泛素介导的降解，增强乳腺癌中 ER-α 的作用。
DOI：
10.1002/advs.202201701
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发表时间：
2022-09
期刊：
影响因子：
15.1
通讯作者：
Yang, Qifeng
中科院分区：
文献类型：
--
作者：
Han, Dianwen;Wang, Lijuan;Long, Li;Su, Peng;Luo, Dan;Zhang, Hanwen;Li, Zheng;Chen, Bing;Zhao, Wenjing;Zhang, Ning;Wang, Xiaolong;Liang, Yiran;Li, Yaming;Hu, Guohong;Yang, Qifeng
雌激素受体α （ER‐α）的作用对激素依赖性乳腺癌至关重要，ER‐α调节失调可导致内分泌治疗出现耐药性。本研究发现TRIM4在他莫昔芬（TAM）耐药的乳腺癌细胞中下调，而TRIM4的缺失与不良预后相关。体外和体内实验证实，TRIM4增加了乳腺癌细胞ER‐α的表达和对TAM的敏感性。机制上，TRIM4被发现靶向SET，并且TRIM4 - SET相互作用是由TRIM4的RING和B - box结构域以及SET的羧基端介导的。此外，我们确定TRIM4催化了SET （K150和K172）的K48连锁多泛素化，促进其蛋白酶体降解和与p53和PP2A的分离。一旦释放，p53和PP2A能够进一步促进ESR1基因的转录，增强mRNA的稳定性。此外，单因素和多因素Cox比例风险回归分析证实，TRIM4表达是ER α阳性乳腺癌患者总生存率和无复发生存率的独立预测因子。综上所述，这些数据突出了一个以前未被发现的机制，并表明TRIM4是一个有价值的生物标志物，可以用来预测乳腺癌患者对内分泌治疗的反应。TRIM4催化SET的K48连锁多泛素化，促进其蛋白酶体降解和与p53和PP2A的分离。p53和PP2A一旦释放，可进一步促进ESR1基因转录，增强mRNA稳定性。这些发现概述了一个有希望的治疗靶点，用于修复乳腺癌和其他与异常SET表达相关的疾病的TAM耐药性。
Estrogen receptor alpha (ER‐α) action is critical for hormone‐dependent breast cancer, and ER‐α dysregulation can lead to the emergence of resistance to endocrine therapy. Here, it is found that TRIM4 is downregulated in tamoxifen (TAM)‐resistant breast cancer cells, while the loss of TRIM4 is associated with an unfavorable prognosis. In vitro and in vivo experiments confirm that TRIM4 increased ER‐α expression and the sensitivity of breast cancer cells to TAM. Mechanistically, TRIM4 is found to target SET, and TRIM4‐SET interactions are mediated by the RING and B‐box domains of TRIM4 and the carboxyl terminus of SET. Moreover, it is determined that TRIM4 catalyzed the K48‐linked polyubiquitination of SET (K150 and K172), promoting its proteasomal degradation and disassociation from p53 and PP2A. Once released, p53 and PP2A are able to further promote ESR1 gene transcription and enhance mRNA stability. Moreover, univariate and multivariate Cox proportional hazards regression analyses confirm that TRIM4 expression is an independent predictor of overall survival and recurrence‐free survival outcomes in patients with ER‐α positive breast cancer. Taken together, the data highlights a previously undiscovered mechanism and suggest that TRIM4 is a valuable biomarker that can be analyzed to predict response to endocrine therapy in breast cancer patients. TRIM4 catalyzes the K48‐linked polyubiquitination of SET, promoting its proteasomal degradation and disassociation from p53 and PP2A. Once released, p53 and PP2A can further promote ESR1 gene transcription and enhance mRNA stability. The findings outline a promising therapeutic target for the remediation of TAM resistance in breast cancer and other diseases associated with aberrant SET expression.
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固定过表达与接受他莫昔芬辅助治疗的原发性乳腺癌患者的无复发生存率较差有关。
影响因子：
3.9
作者：
Huang YH;Chu PY;Chen JL;Huang CT;Lee CH;Lau KY;Wang WL;Wang YL;Lien PJ;Tseng LM;Liu CY
通讯作者：
Liu CY
DOI：
10.1158/1078-0432.ccr-13-2575
发表时间：
2014-04-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
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通讯作者：
Druker BJ
影响因子：
11.2
作者：
Creighton, CJ;Hilger, AM;El-Ashry, D
通讯作者：
El-Ashry, D
影响因子：
4
作者：
Angeloni, SV;Martin, MB;Saceda, M
通讯作者：
Saceda, M
影响因子：
--
作者：
Fan, MY;Park, A;Nephew, KP
通讯作者：
Nephew, KP