Genome-wide CRISPR-Cas9 knockout library screening identified PTPMT1 in cardiolipin synthesis is crucial to survival in hypoxia in liver cancer

• Published in: Cell reports (Cambridge) Vol. 34; no. 4; p. 108676
• Main Authors: Bao, Macus Hao-Ran, Yang, Chunxue, Tse, Aki Pui-Wah, Wei, Lai, Lee, Derek, Zhang, Misty Shuo, Goh, Chi Ching, Chiu, David Kung-Chun, Yuen, Vincent Wai-Hin, Law, Cheuk-Ting, Chin, Wai-Ching, Chui, Noreen Nog-Qin, Wong, Bowie Po-Yee, Chan, Cerise Yuen-Ki, Ng, Irene Oi-Lin, Chung, Clive Yik-Sham, Wong, Chun-Ming, Wong, Carmen Chak-Lui
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.01.2021
• Subjects: Animals; cardiolipin; Cardiolipins - biosynthesis; Cardiolipins - genetics; Cell Hypoxia - physiology; CRISPR library screening; CRISPR-Cas Systems; electron transport chain; HCT116 Cells; Hep G2 Cells; Heterografts; Humans; hypoxia; liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; metabolism; Mice; Mice, Inbred BALB C; Mice, Nude; mitochondria; oxidative stress; PC-3 Cells; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; ROS; hypoxia; electron transport chain; mitochondria; ROS; CRISPR library screening; liver cancer; metabolism; cardiolipin; oxidative stress
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108676

Hypoxia, low oxygen (O2), 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. [Display omitted] •CRISPR-Cas9 library screen identifies that PTPMT1 is a vital gene for hypoxic survival•PTPMP1 synthesizes CL to trap electrons at mitochondria to prevent ROS buildup•Knockout or inhibition of PTPMT1 induces ROS and apoptosis in hypoxic cancer cells•PTPMT1 is a targetable metabolic vulnerability to combat hypoxic solid tumors Bao et al. use CRISPR library screening to identify PTPMT1, an important gene for hypoxic survival of HCC cells. PTPMT1 synthesizes cardiolipin, a crucial component of mitochondrial membrane, to maintain mitochondrial integrity, trap electrons, and prevent excessive ROS accumulation under hypoxia. PTPMT1 is a targetable vulnerability to combat hypoxic cancers.