The oncoprotein MUC1 facilitates breast cancer progression by promoting Pink1-dependent mitophagy via ATAD3A destabilization.
The oncoprotein MUC1 facilitates breast cancer progression by promoting Pink1-dependent mitophagy via ATAD3A destabilization.
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癌蛋白 MUC1 通过 ATAD3A 不稳定促进 Pink1 依赖性线粒体自噬，从而促进乳腺癌进展
DOI：
10.1038/s41419-022-05345-z
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发表时间：
2022-10-26
影响因子：
9
通讯作者：
Huang, Lei
中科院分区：
文献类型：
--
作者：
Li, Quanfu;Chu, Yunkai;Li, Shengze;Yu, Liping;Deng, Huayun;Liao, Chunhua;Liao, Xiaodong;Yang, Chihyu;Qi, Min;Cheng, Jinke;Chen, Guoqiang;Huang, Lei
线粒体自噬是控制线粒体质量的重要过程，其失调可促进癌症。癌蛋白粘蛋白1（MUC 1）靶向线粒体以减弱药物诱导的细胞凋亡。然而，关于MUC 1是否以及如何有助于癌细胞中的线粒体稳态，人们知之甚少。我们确定了MUC 1在促进线粒体自噬中的新作用。增加的线粒体自噬与MUC 1向线粒体的易位相结合，在线粒体中MUC 1与ATP酶家族AAA结构域3A（ATAD 3A）相互作用并诱导其降解，从而保护PTEN诱导的激酶1（Pink 1）免受ATAD 3A介导的切割。有趣的是，MUC 1诱导的线粒体自噬与癌细胞的致癌性增加有关。类似地，线粒体自噬的抑制在体外和体内显著抑制MUC 1诱导的癌细胞活性。一致的是，MUC 1和ATAD 3A蛋白水平在乳腺癌患者的肿瘤组织中呈现负相关。我们的数据验证了MUC 1/ATAD 3A/Pink 1轴介导的线粒体自噬构成了维持癌细胞恶性的新机制，为MUC 1阳性癌症提供了新的治疗方法。
Mitophagy is a vital process that controls mitochondria quality, dysregulation of which can promote cancer. Oncoprotein mucin 1 (MUC1) targets mitochondria to attenuate drug-induced apoptosis. However, little is known about whether and how MUC1 contributes to mitochondrial homeostasis in cancer cells. We identified a novel role of MUC1 in promoting mitophagy. Increased mitophagy is coupled with the translocation of MUC1 to mitochondria, where MUC1 interacts with and induces degradation of ATPase family AAA domain-containing 3A (ATAD3A), resulting in protection of PTEN-induced kinase 1 (Pink1) from ATAD3A-mediated cleavage. Interestingly, MUC1-induced mitophagy is associated with increased oncogenicity of cancer cells. Similarly, inhibition of mitophagy significantly suppresses MUC1-induced cancer cell activity in vitro and in vivo. Consistently, MUC1 and ATAD3A protein levels present an inverse relationship in tumor tissues of breast cancer patients. Our data validate that MUC1/ATAD3A/Pink1 axis-mediated mitophagy constitutes a novel mechanism for maintaining the malignancy of cancer cells, providing a novel therapeutic approach for MUC1-positive cancers.
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