1. Genome-wide CRISPR-Cas9 knockout library screening identified PTPMT1 in cardiolipin synthesis is crucial to survival in hypoxia in liver cancer.
- Author
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Bao MH, Yang C, Tse AP, Wei L, Lee D, Zhang MS, Goh CC, Chiu DK, Yuen VW, Law CT, Chin WC, Chui NN, Wong BP, Chan CY, Ng IO, Chung CY, Wong CM, and Wong CC
- Subjects
- Animals, CRISPR-Cas Systems, Cardiolipins genetics, Cell Hypoxia physiology, HCT116 Cells, Hep G2 Cells, Heterografts, Humans, Liver Neoplasms genetics, Liver Neoplasms pathology, Male, Mice, Mice, Inbred BALB C, Mice, Nude, PC-3 Cells, PTEN Phosphohydrolase genetics, Cardiolipins biosynthesis, Liver Neoplasms metabolism, PTEN Phosphohydrolase metabolism
- Abstract
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)-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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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