Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA; Beijing You'an Hospital, Capital Medical University, Beijing 100069, China; Beijing Institute of Hepatology, Beijing 100069, China.
Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA.
Mol Cell. 2017 Oct 19;68(2):281-292.e5. doi: 10.1016/j.molcel.2017.09.022. Epub 2017 Oct 12.
Autophagy is required for benign hepatic tumors to progress into malignant hepatocellular carcinoma. However, the mechanism is unclear. Here, we report that mitophagy, the selective removal of mitochondria by autophagy, positively regulates hepatic cancer stem cells (CSCs) by suppressing the tumor suppressor p53. When mitophagy is enhanced, p53 co-localizes with mitochondria and is removed by a mitophagy-dependent manner. However, when mitophagy is inhibited, p53 is phosphorylated at serine-392 by PINK1, a kinase associated with mitophagy, on mitochondria and translocated into the nucleus, where it binds to the NANOG promoter to prevent OCT4 and SOX2 transcription factors from activating the expression of NANOG, a transcription factor critical for maintaining the stemness and the self-renewal ability of CSCs, resulting in the reduction of hepatic CSC populations. These results demonstrate that mitophagy controls the activities of p53 to maintain hepatic CSCs and provide an explanation as to why autophagy is required to promote hepatocarcinogenesis.
自噬对于良性肝肿瘤进展为恶性肝细胞癌是必需的。然而，其机制尚不清楚。在这里，我们报告说，通过自噬选择性去除线粒体的线粒体自噬通过抑制肿瘤抑制因子 p53 来正向调节肝肿瘤干细胞（CSC）。当自噬增强时，p53 与线粒体共定位，并通过依赖于自噬的方式被去除。然而，当自噬受到抑制时，p53 在线粒体上被与自噬相关的激酶 PINK1 磷酸化在丝氨酸-392 处，然后转移到细胞核，在细胞核中与 NANOG 启动子结合，防止 OCT4 和 SOX2 转录因子激活 NANOG 的转录，NANOG 是维持 CSCs 干性和自我更新能力的关键转录因子，导致肝 CSC 群体减少。这些结果表明，线粒体自噬控制着 p53 的活性以维持肝 CSCs，并解释了为什么自噬对于促进肝癌发生是必需的。
