Department of Pathology, The University of Hong Kong, Hong Kong.
Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong.
Cell Rep. 2021 Jan 26;34(4):108676. doi: 10.1016/j.celrep.2020.108676.
Hypoxia, low oxygen (O), is a key feature of all solid cancers, including hepatocellular carcinoma (HCC). Genome-wide CRISPR-Cas9 knockout library screening is used to identify reliable therapeutic targets responsible for hypoxic survival in HCC. We find that protein-tyrosine phosphatase mitochondrial 1 (PTPMT1), an important enzyme for cardiolipin (CL) synthesis, is the most significant gene and ranks just after hypoxia-inducible factor (HIF)-1α and HIF-1β as crucial to hypoxic survival. CL constitutes the mitochondrial membrane and ensures the proper assembly of electron transport chain (ETC) complexes for efficient electron transfer in respiration. ETC becomes highly unstable during hypoxia. Knockout of PTPMT1 stops the maturation of CL and impairs the assembly of ETC complexes, leading to further electron leakage and ROS accumulation at ETC in hypoxia. Excitingly, HCC cells, especially under hypoxic conditions, show great sensitivity toward PTPMT1 inhibitor alexidine dihydrochloride (AD). This study unravels the protective roles of PTPMT1 in hypoxic survival and cancer development.
缺氧，即低氧（O），是所有实体瘤的一个关键特征，包括肝细胞癌（HCC）。全基因组 CRISPR-Cas9 敲除文库筛选用于鉴定负责 HCC 缺氧存活的可靠治疗靶点。我们发现，蛋白酪氨酸磷酸酶线粒体 1（PTPMT1）是一种重要的磷脂酰丝氨酸合成酶，是最重要的基因，仅次于缺氧诱导因子（HIF）-1α和 HIF-1β，对缺氧存活至关重要。CL 构成了线粒体膜，并确保电子传递链（ETC）复合物的正确组装，以在呼吸过程中实现有效的电子传递。ETC 在缺氧时变得极不稳定。PTPMT1 的敲除阻止了 CL 的成熟，并损害了 ETC 复合物的组装，导致在缺氧时 ETC 中的电子泄漏和 ROS 积累进一步增加。令人兴奋的是，HCC 细胞，尤其是在缺氧条件下，对 PTPMT1 抑制剂盐酸阿霉素（AD）表现出高度敏感性。这项研究揭示了 PTPMT1 在缺氧存活和癌症发展中的保护作用。
