A20-mediated deubiquitination of ERα in the microenvironment of CD163+ macrophages sensitizes endometrial cancer cells to estrogen. (1st February 2019)

• Record Type: Journal Article
• Authors: Lv, Qiaoying; Xie, Liying; Cheng, Yali; Shi, Yue; Shan, Weiwei; Ning, Chengcheng; Xie, Bingying; Yang, Bingyi; Luo, Xuezhen; He, Qizhi; Zhu, Qin; Zhang, Yingli; Zhang, Zhenbo; Wang, Chenji; Chen, Xiaojun; Xu, Congjian
• Is Part Of: Cancer letters. Volume 442(2019)
• Page Start: 137
• Page End: 147
• Publication Date: 2019-02-01
• Subjects: Endometrial cancer -- CD163+ macrophages -- ERα -- A20 -- Deubiquitination; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.10.019
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Continuous estrogen signaling is thought to be the main mechanism causing endometrial cancer (EC). Studies have demonstrated that CD163 + macrophages could promote the development of estrogen-dependent EC, but the mechanisms involved remain unclear. We found that CD163 + macrophages were the dominant macrophages in atypical endometrial hyperplasia and cancer, and their infiltration was positively associated with ERα expression. CD163 + macrophages mainly increased ERα protein levels but with little upregulatory effect on ESR1 (ERα coding gene) transcripts. The ubiquitin-editing enzyme A20, screened from the endometrial microarray obtained from mice receiving a high-fat diet and sustained estrogen-intervened, was highly expressed in endometrial lesions rich with CD163 + macrophages, and positively correlated with ERα expression. Similarly, A20 and ERα were both upregulated by CD163 + macrophages via cytokines such as IL1α, IL17A and TNFα. Mechanistically, A20 overexpression in EC cells prolonged ERα protein half-life without affecting ESR1 transcripts. A20 increased functional ERα protein levels and enhanced estrogen-driven EC cell proliferation through preventing ERα protein degradation by its deubiquitinase activity. Our study revealed that A20-mediated deubiquitination of ERα might be an important mechanism by which CD163 + macrophages sensitize EC cells to estrogen. Highlights: CD163 + macrophages sensitize EC cells to estrogen by mainly upregulating ERα protein. A20 and ERα were highly expressed in endometrial lesions rich with CD163 + macrophages. CD163 + macrophages upregulated A20 and ERα via cytokines. A20 forms a complex with ERα protein in cell nuclei to stabilize ERα protein. A20 stabilizes ERα protein through deubiquitination of ERα protein.