A20-mediated deubiquitination of ER alpha in the microenvironment of CD163(+) macrophages sensitizes endometrial cancer cells to estrogen

摘要

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 ER alpha expression. CD163(+) macrophages mainly increased ERa protein levels but with little upregulatory effect on ESR1 (ER alpha 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 ER alpha expression. Similarly, A20 and ER alpha were both upregulated by CD163(+) macrophages via cytokines such as ILla, IL17A and TNF alpha. Mechanistically, A20 overexpression in EC cells prolonged ER alpha protein half-life without affecting ESR1 transcripts. A20 increased functional ER alpha protein levels and enhanced estrogen-driven EC cell proliferation through preventing ER alpha protein degradation by its deubiquitinase activity. Our study revealed that A20-mediated deubiquitination of ER alpha might be an important mechanism by which CD163(+) macrophages sensitize EC cells to estrogen.