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

Oncogene volume 41, pages 2897–2908 (2022)Cite this article

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Abstract

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.

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Fig. 1: XAF1 promotes E2-induced apoptosis in ERα+ cells.
Fig. 2: E2 activation of XAF1 transcription and its repression by ERα.
Fig. 3: XAF1 stimulation of ERα ubiquitination and degradation.
Fig. 4: XAF1 binds directly to ERα.
Fig. 5: XAF1 interacts directly with BRCA1 to facilitate ERα ubiquitination.
Fig. 6: Role of a XAF1-ERα axis in E2-mediated tumor regression.
Fig. 7: Schematic representation of the antagonistic interplay of XAF1 and ERα and its role in estrogen-mediated cell-fate decisions.

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All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Funding

This work was supported in part by the National Cancer Center (HA17C0034, SGC), the National Research Foundation of Korea (NRF-2021R1A2B03002487, SGC), and Korea University Grant (K2006781, SGC), Republic of Korea.

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  1. Byung-Kyu Ryu

    Present address: Department of Neurosurgery, School of Medicine, Korea University, Seoul, 02841, Republic of Korea

Authors and Affiliations

  1. Department of Life Sciences, College of Life Sciences and Technology, Korea University, Seoul, 02841, Republic of Korea

    Ji-Sun Lim, Kyung-Woo Lee, Kyung-Phil Ko, Seong-In Jeong, Byung-Kyu Ryu, Min-Goo Lee & Sung-Gil Chi

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JSL, KWL, KPK, SIJ, BKR, and MGL performed experiments. MGL and SGC provided interpretation of the data. JSL and SGC wrote the manuscript. SGC is responsible for designing and funding collections. All authors have approved this manuscript.

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Correspondence to Sung-Gil Chi.

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Lim, JS., Lee, KW., Ko, KP. et al. XAF1 destabilizes estrogen receptor α through the assembly of a BRCA1-mediated destruction complex and promotes estrogen-induced apoptosis. Oncogene 41, 2897–2908 (2022). https://doi.org/10.1038/s41388-022-02315-9

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