Genome-wide CRISPR-Cas9 knockout library screening identified PTPMT1 in cardiolipin synthesis is crucial to survival in hypoxia in liver cancer
Genome-wide CRISPR-Cas9 knockout library screening identified PTPMT1 in cardiolipin synthesis is crucial to survival in hypoxia in liver cancer
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DOI：
10.1016/j.celrep.2020.108676
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发表时间：
2021-01-26
期刊：
影响因子：
8.8
通讯作者：
Wong, Carmen Chak-Lui
中科院分区：
文献类型：
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作者：
Bao, Macus Hao-Ran;Yang, Chunxue;Wong, Carmen Chak-Lui
缺氧，低氧（O-2），是所有实体癌的关键特征，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中低氧存活的可靠治疗靶标。我们发现，蛋白酪氨酸磷酸酶线粒体1（PTPMT 1），心磷脂（CL）合成的重要酶，是最重要的基因和排名仅次于缺氧诱导因子（HIF）-1 α和HIF-1 β的缺氧生存至关重要。CL构成线粒体膜，并确保电子传递链（ETC）复合物的正确组装，以实现呼吸中的有效电子传递。ETC在缺氧期间变得高度不稳定。敲除PTPMT 1会阻止CL的成熟并损害ETC复合物的组装，导致缺氧时ETC处进一步的电子泄漏和ROS积累。令人兴奋的是，肝癌细胞，特别是在缺氧条件下，对PTPMT 1抑制剂二氢阿来西定（AD）表现出极大的敏感性。这项研究揭示了PTPMT 1在低氧生存和癌症发展中的保护作用。
Hypoxia, low oxygen (O-2), 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)-1 alpha and HIF-1 beta 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 dihydrochioride (AD). This study unravels the protective roles of PTPMT1 in hypoxic survival and cancer development.