Lim Ji-Sun, Lee Kyung-Woo, Ko Kyung-Phil, Jeong Seong-In, Ryu Byung-Kyu, Lee Min-Goo, Chi Sung-Gil
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.
Oncogene. 2022 May;41(20):2897-2908. doi: 10.1038/s41388-022-02315-9. Epub 2022 Apr 16.
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.
X连锁凋亡抑制相关因子1（XAF1）是一种促凋亡肿瘤抑制因子，在多种人类癌症中经常失活。然而，其作为乳腺癌发病机制中抑制因子的候选地位仍不明确。在此，我们报告XAF1在雌激素（E2）介导的细胞命运决定中起分子开关作用，促进细胞凋亡而非细胞增殖。主要在雌激素受体α（ERα）阳性肿瘤细胞与ERα阴性肿瘤细胞中观察到XAF1启动子高甲基化，且与对E2的凋亡反应减弱相关。XAF1通过G蛋白偶联雌激素受体介导的非基因组途径被E2激活，并诱导ERα降解和凋亡，而在E2刺激细胞增殖时，它被ERα抑制。XAF1-ERα相互拮抗决定了E2信号传导的结果，其改变与E2耐药肿瘤的发生有关。机制上，XAF1通过乳腺癌相关基因1（BRCA1）介导的破坏复合物的组装使ERα不稳定。XAF1分别通过锌指（ZF）结构域5/6和4与ERα和BRCA1相互作用，缺乏这些结构域之一的突变体无法驱动ERα泛素化和凋亡。XAF1缺失可消除E2诱导的XAF1肿瘤消退，而XAF1恢复可使XAF1肿瘤恢复E2反应。在原发性乳腺肿瘤中，XAF1和ERα表达呈负相关，且XAF1表达与ERα阳性而非ERα阴性癌症患者的总生存期相关。总之，本研究揭示了XAF1-ERα拮抗作为控制E2介导的细胞命运决定的关键因素的重要作用，阐明了XAF1改变在乳腺肿瘤发生中的机制后果。
