CRISPR/Cas9 Screens Reveal that Hexokinase 2 Enhances Cancer Stemness and Tumorigenicity by Activating the ACSL4‐Fatty Acid β‐Oxidation Pathway

• Published in: Advanced science Vol. 9; no. 21; pp. e2105126 - n/a
• Main Authors: Li, Hongquan, Song, Junjiao, He, Yifei, Liu, Yizhe, Liu, Zhen, Sun, Weili, Hu, Weiguo, Lei, Qun‐Ying, Hu, Xin, Chen, Zhiao, He, Xianghuo
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01-07-2022; John Wiley and Sons Inc; Wiley
• Subjects: ACSL4; cancer cell stemness; Candidates; Coenzyme A Ligases - genetics; Coenzyme A Ligases - metabolism; CRISPR; CRISPR-Cas Systems - genetics; Enzymes; fatty acid β‐oxidation; Fatty Acid-Binding Proteins - genetics; Fatty Acid-Binding Proteins - metabolism; Fatty acids; Fatty Acids - metabolism; Gene expression; Genomes; Hepatitis; Hexokinase - genetics; Hexokinase - metabolism; hexokinase 2; Humans; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Metabolism; Metastasis; Neoplastic Stem Cells - metabolism; Signal transduction; Stem cells; Tumors; ACSL4; fatty acid β-oxidation; cancer cell stemness; hexokinase 2
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202105126

Metabolic reprogramming is often observed in carcinogenesis, but little is known about the aberrant metabolic genes involved in the tumorigenicity and maintenance of stemness in cancer cells. Sixty‐seven oncogenic metabolism‐related genes in liver cancer by in vivo CRISPR/Cas9 screening are identified. Among them, acetyl‐CoA carboxylase 1 (ACC1), aldolase fructose‐bisphosphate A (ALDOA), fatty acid binding protein 5 (FABP5), and hexokinase 2 (HK2) are strongly associated with stem cell properties. HK2 further facilitates the maintenance and self‐renewal of liver cancer stem cells. Moreover, HK2 enhances the accumulation of acetyl‐CoA and epigenetically activates the transcription of acyl‐CoA synthetase long‐chain family member 4 (ACSL4), leading to an increase in fatty acid β‐oxidation activity. Blocking HK2 or ACSL4 effectively inhibits liver cancer growth, and GalNac‐siHK2 administration specifically targets the growth of orthotopic tumor xenografts. These results suggest a promising therapeutic strategy for the treatment of liver cancer.
Hexokinase 2 (HK2) is a novel stimulus for liver cancer stem cells. The newly identified HK2‐acyl‐CoA synthetase long chain family member 4 (ACSL4)‐fatty acid β‐oxidation axis is an ideal therapeutic target for hepatocellular carcinoma (HCC), and GalNac‐conjugated siHK2 opens an avenue to develop a novel strategy of precision therapy for the treatment of HCC.