XAF1 destabilizes estrogen receptor α through the assembly of a BRCA1-mediated destruction complex and promotes estrogen-induced apoptosis.

Autor: Lim JS; Department of Life Sciences, College of Life Sciences and Technology, Korea University, Seoul, 02841, Republic of Korea., Lee KW; Department of Life Sciences, College of Life Sciences and Technology, Korea University, Seoul, 02841, Republic of Korea., Ko KP; Department of Life Sciences, College of Life Sciences and Technology, Korea University, Seoul, 02841, Republic of Korea., Jeong SI; Department of Life Sciences, College of Life Sciences and Technology, Korea University, Seoul, 02841, Republic of Korea., Ryu BK; Department of Life Sciences, College of Life Sciences and Technology, Korea University, Seoul, 02841, Republic of Korea.; Department of Neurosurgery, School of Medicine, Korea University, Seoul, 02841, Republic of Korea., Lee MG; Department of Life Sciences, College of Life Sciences and Technology, Korea University, Seoul, 02841, Republic of Korea., Chi SG; Department of Life Sciences, College of Life Sciences and Technology, Korea University, Seoul, 02841, Republic of Korea. chi6302@korea.ac.kr.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2022 May; Vol. 41 (20), pp. 2897-2908. Date of Electronic Publication: 2022 Apr 16.
DOI: 10.1038/s41388-022-02315-9
Abstrakt: X-linked inhibitor of apoptosis-associated factor 1 (XAF1) is a pro-apoptotic tumor suppressor that is frequently inactivated in multiple human cancers. However, its candidacy as a suppressor in the pathogenesis of breast cancer remains undefined. Here, we report that XAF1 acts as a molecular switch in estrogen (E2)-mediated cell-fate decisions favoring apoptosis over cell proliferation. XAF1 promoter hypermethylation is observed predominantly in estrogen receptor α (ERα)-positive versus ERα-negative tumor cells and associated with attenuated apoptotic response to E2. XAF1 is activated by E2 through a G protein-coupled estrogen receptor-mediated non-genomic pathway and induces ERα degradation and apoptosis while it is repressed by ERα for E2 stimulation of cell proliferation. The XAF1-ERα mutual antagonism dictates the outcomes of E2 signaling and its alteration is linked to the development of E2-resistant tumors. Mechanistically, XAF1 destabilizes ERα through the assembly of breast cancer-associated gene 1 (BRCA1)-mediated destruction complex. XAF1 interacts with ERα and BRCA1 via the zinc finger (ZF) domains 5/6 and 4, respectively, and the mutants lacking either of these domains fail to drive ERα ubiquitination and apoptosis. E2-induced regression of XAF1 +/+ tumors is abolished by XAF1 depletion while XAF1 -/- tumors recover E2 response by XAF1 restoration. XAF1 and ERα expression show an inverse correlation in primary breast tumors, and XAF1 expression is associated with the overall survival of patients with ERα-positive but not ERα-negative cancer. Together, this study uncovers an important role for the XAF1-ERα antagonism as a linchpin to govern E2-mediated cell-fate decisions, illuminating the mechanistic consequence of XAF1 alteration in breast tumorigenesis.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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