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

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

doi:10.1016/j.celrep.2020.108676

Cited by 37 publications

(27 citation statements)

References 42 publications

(52 reference statements)

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“…Interestingly, functional screening has identified HIF-independent genes important for hypoxic HCC cell survival, which could be exploited as therapeutic targets. Our group employed genome-wide CRISPR/Cas9 library screening and identified protein-tyrosine phosphatase mitochondrial 1 (PTPMT1) as a crucial metabolic regulator for survival of HCC cells under hypoxia [ 118 ]. PTPMT1 synthesizes cardiolipin, which is the major constituent of the mitochondrial inner membrane (MIM), which anchors the ETC complexes to allow efficient electron transfer.…”

Section: Targeting Hypoxic Hcc To Overcome Drug Resistancementioning

confidence: 99%

“…Inhibition of PTPMT1 led to excessive electron leakage at the ETC, rendering cell death in hypoxic HCC cells. PTPMT1 inhibitor significantly suppressed growth and progression of hypoxic HCC [ 118 ], making it a promising drug for combination treatment to combat drug resistant HCC. Genes that are functionally important for hypoxic cell survival might not necessarily be induced by HIFs therefore could also be attractive therapeutic targets to overcome drug resistance in hypoxic HCC.…”

Section: Targeting Hypoxic Hcc To Overcome Drug Resistancementioning

confidence: 99%

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Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer

Bao

Wong

2021

Cells

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171

121

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Hypoxia, low oxygen (O2) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus on the roles of hypoxia-inducible factor (HIF)-mediated metabolic reprogramming in drug resistance in HCC. Combination therapies targeting hypoxia-induced metabolic enzymes to overcome drug resistance will also be summarized. Acquisition of drug resistance is the major cause of unsatisfactory clinical outcomes of existing HCC treatments. Extra efforts to identify novel mechanisms to combat refractory hypoxic HCC are warranted for the development of more effective treatment regimens for HCC patients.

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Section: Targeting Hypoxic Hcc To Overcome Drug Resistancementioning

confidence: 99%

Section: Targeting Hypoxic Hcc To Overcome Drug Resistancementioning

confidence: 99%

Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer

Bao

Wong

2021

Cells

Self Cite

171

121

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“…Above that, a PTPMT1 inhibitor, alexidine dihydrochloride (AD), slowed cancer growth too. This happened again more effective under hypoxia than under normoxia ( Bao et al, 2021 ). Furthermore, they used three different mouse models to investigate PTPMT1 in vivo : a hydrodynamic tail vein injection (HDTVi) model, where they injected a p53 KO by CRISPR-Cas9-KO plasmid and c-myc oe by sleeping beauty (SB) transposon system plasmid in C57BL/6N mice; a subcutaneous tumor model with nude mice using MHCC97L cells and orthotopic tumors with luciferase-labeled MHCC97L cells in nude mice.…”

Section: Hepatocellular Cancermentioning

confidence: 95%

CRISPR/Cas9 in Gastrointestinal Malignancies

Jefremow

Waldner

2021

Front. Cell Dev. Biol.

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Gastrointestinal (GI) cancers such as colorectal cancer (CRC), gastric cancer (GC), esophageal cancer (EG), pancreatic duct adenocarcinoma (PDAC) or hepatocellular cancer (HCC) belong to the most commonly diagnosed types of cancer and are among the most frequent causes of cancer related death worldwide. Most types of GI cancer develop in a stepwise fashion with the occurrence of various driver mutations during tumor progression. Understanding the precise function of mutations driving GI cancer development has been regarded as a prerequisite for an improved clinical management of GI malignancies. During recent years, CRISPR/Cas9 has developed into a powerful tool for genome editing in cancer research by knocking in and knocking out even multiple genes at the same time. Within this review, we discuss recent applications for CRISPR/Cas9-based genome editing in GI cancer research including CRC, GC, EG, PDAC and HCC. These applications include functional studies of candidate genes in cancer cell lines or organoids in vitro as well as in murine cancer models in vivo, library screening for the identification of previously unknown driver mutations and even gene therapy of GI cancers.

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“…Lower cardiolipin concentrations may result from altered human cardiolipin synthase 1 [69], lysocardiolipin acyltransferase [70], or protein-tyrosine phosphatase mitochondrial 1 [71] expression. These enzymes are involved in cardiolipin biosynthesis and remodeling and have been observed to be differentially expressed in some NSCLC subtypes [72].…”

Section: Potential Clinical Implicationsmentioning

confidence: 99%

Untargeted Lipidomics of Non-Small Cell Lung Carcinoma Demonstrates Differentially Abundant Lipid Classes in Cancer vs. Non-Cancer Tissue

2021

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Lung cancer remains the leading cause of cancer death worldwide and non-small cell lung carcinoma (NSCLC) represents 85% of newly diagnosed lung cancers. In this study, we utilized our untargeted assignment tool Small Molecule Isotope Resolved Formula Enumerator (SMIRFE) and ultra-high-resolution Fourier transform mass spectrometry to examine lipid profile differences between paired cancerous and non-cancerous lung tissue samples from 86 patients with suspected stage I or IIA primary NSCLC. Correlation and co-occurrence analysis revealed significant lipid profile differences between cancer and non-cancer samples. Further analysis of machine-learned lipid categories for the differentially abundant molecular formulas identified a high abundance sterol, high abundance and high m/z sphingolipid, and low abundance glycerophospholipid metabolic phenotype across the NSCLC samples. At the class level, higher abundances of sterol esters and lower abundances of cardiolipins were observed suggesting altered stearoyl-CoA desaturase 1 (SCD1) or acetyl-CoA acetyltransferase (ACAT1) activity and altered human cardiolipin synthase 1 or lysocardiolipin acyltransferase activity respectively, the latter of which is known to confer apoptotic resistance. The presence of a shared metabolic phenotype across a variety of genetically distinct NSCLC subtypes suggests that this phenotype is necessary for NSCLC development and may result from multiple distinct genetic lesions. Thus, targeting the shared affected pathways may be beneficial for a variety of genetically distinct NSCLC subtypes.

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

Cited by 37 publications

References 42 publications

Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer

Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer

CRISPR/Cas9 in Gastrointestinal Malignancies

Untargeted Lipidomics of Non-Small Cell Lung Carcinoma Demonstrates Differentially Abundant Lipid Classes in Cancer vs. Non-Cancer Tissue

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