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HIF-1α-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation

查看全文 作　　者：Qing [1,2]Li;Yong [3]Ni;Liren [1]Zhang;Runqiu [4,5]Jiang;Jing [6]Xu;Hong [7]Yang;Yuanchang [1]Hu;Jiannan [1]Qiu;Liyong [1]Pu;Jinhai [8]Tang;Xuehao [1,2]Wang 高影响力作者 机构地区：[1]Hepatobiliary Center,The First Affiliated Hospital of Nanjing Medical University,Key Laboratory of Liver Transplantation,Chinese Academy of Medical Sciences,NHC Key Laboratory of Living Donor Liver Transplantation(Nanjing Medical University),Nanjing,Jiangsu Province,China;[2]School of Medicine,Southeast University,Nanjing,China;[3]department of Hepatopancreatobiliary Surgery,Shenzhen Second People's Hospital,The First Affiliated Hospital of Shenzhen University,Shenzhen,Guangdong,China;[4]Department of Hepatobiliary Surgery,The Affiliated Drum Tower Hospital of Nanjing University Medical School,Nanjing,Jiangsu Province,People's Republic of China;[5]Medical School of Nanjing University,Nanjing,Jiangsu,China;[6]Department of Oncology,The First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu Province,China;[7]Department of Immunology,Key Laboratory of Immune Microenvironment and Disease,Nanjing Medical University,Nanjing,Jiangsu Province,China;[8]Department of General Surgery,The First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu Province,China高影响力机构 出　　处：《Signal Transduction and Targeted Therapy》索引2021年第6卷第3期,共13页高影响力期刊 基　　金：supported by the Major Program of the National Natural Science Foundation of China(Grant No.81530048,31930020);Key Laboratory of Liver Transplantation,Chinese Academy of Medical Sciences(Grant No.2017PT32008,2018PT31043,2019PT320015);the National Natural Science Foundation of China(Grant No.81870488,81872365,81972266,81772569);the Shenzhen Foundation of Science and Technology(Grant No.JCYJ20170817172116272);the Sanm ing Project of Medicine in Shenzhen(Grant No.SZSM201812079). 摘　　要：N6-methyladenosine(m6A),and its reader protein YTHDF1,play a pivotal role in human tumorigenesis by affecting nearly everystage of RNA metabolism.Autophagy activation is one of the ways by which cancer cells survive hypoxia.However,the possibleinvolvement of m6A modification of mRNA in hypoxia-induced autophagy was unexplored in human hepatocellular carcinoma(HCO).In this study,specific variations in YTHDF1 expression were detected in YTHDF1-overexpressing,knockout,and-knockdownHCC cells,HCC organoids,and HCC patient-derived xenograft(PDX)murine models.YTHDF1 expression and hypoxia inducedautophagy were significantly correlated in vitro;signifhcant overexpression of YTHDF1 in HCC tissues was associated with poorprognosis,Multivariate cox regression analysis identihed YTHDF1 expression as an independent prognostic factor in patients withHCC.Multiple HC models conhrmed that YTHDF1 deficiency inhibited HCC autophagy,growth,and metastasis.Luciferase reporterassays and chromatin immunoprecipitation demonstrated that HlIF-1a regulated YTHDF1 transcription by directly binding to itspromoter region under hypoxia.The results of methylated RNA immunoprecipitation sequencing,proteomics,and polysomeprofling indicated that YTHDF1 contibuted to the translation of autophagy-related genes ATG2A and ATG14 by binding to m6A-modifhed ATG2A and ATG14 mRNA,thus facilitating autophagy and autophagy-related malignancy of HCC.Taken together,HlE-1d-induced YTHDF1 expression was associated with hypoxia-induced autophagy and autophagy-related HCC progression via promoting translation of autophagy-related genes ATG2A and ATG14 in a m6A-dependent manner.Our fndings suggest thatYTHDF1 is a potential prognostic biomarker and therapeutic target for patients with HCC. 关 键 词：MALIGNANCY HEPATOCELLULAR inhibited
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