ALKBH1 promotes lung cancer by regulating m6A RNA demethylation.

Autor: Li H; Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China; Institute of Pharmacy, Pharmaceutical College of Henan University, Jinming District, Kaifeng, Henan Province 475004, China., Zhang Y; Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China., Guo Y; Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China., Liu R; Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China., Yu Q; Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China., Gong L; Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China., Liu Z; Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China. Electronic address: liuzq@gzucm.edu.cn., Xie W; MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, The Sun Yat-Sen University, Guangzhou, Guangdong 510006, China. Electronic address: xiewei6@mail.sysu.edu.cn., Wang C; Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China. Electronic address: wangcaiyan@gzucm.edu.cn.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2021 Jul; Vol. 189, pp. 114284. Date of Electronic Publication: 2020 Oct 14.
DOI: 10.1016/j.bcp.2020.114284
Abstrakt: Lung cancer has surpassed breast cancer as the leading cause of cancer death in females in developed countries and the leading cause of cancer death in males. Despite extensive research on lung cancer, the pathogenesis of lung cancer is not fully understood. ALKBH1 is a 2-oxoglutarate and Fe (II)-dependent dioxygenase responsible for the demethylation of 6-methyladenine (m6A) in RNA and is essential to multiple cellular processes in human. Numerous recent studies suggest that ALKBH1 plays a role in tumorigenesis and tumor progression, but the role of ALKBH1 in lung cancer is largely unknown. In this study, we demonstrated that the expression levels of ALKBH1 in lung cancer tissues and cells were up regulated. The invasion and migration abilities of lung cancer cells were significantly suppressed in vitro upon the silencing of ALKBH1 while they were significantly promoted upon its overexpression. We next characterized the enzyme biochemically by analyzing the contribution of essential residues Y184, H231, D233, H287, R338, and R344 to its m6A demethylation activity. Lastly, our 3.1-Å crystal structure of mouse ALKBH1 revealed that the N-terminal domain of the protein forms close contacted with the core catalytic domain and might be responsible for the recognition of nucleic acid substrates. In summary, our combined cellular, biochemical, and structural results provide insight into the potential ALKBH1-based drug design for cancer therapies.
(Copyright © 2020. Published by Elsevier Inc.)
Databáze: MEDLINE
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