HBXIP induces PARP1 via WTAP-mediated m^(6)A modification and CEBPA-activated transcription in cisplatin resistance to hepatoma  

作　　者：Xue-li Fu Shi-man Guo Jia-qi Ma Fang-yuan Ma Xue Wang Yan-xin Tang Ye Li Wei-ying Zhang Li-hong Ye 

机构地区：[1]State Key Laboratory of Medicinal Chemical Biology,Tianjin Key Laboratory of Protein Sciences,Department of Biochemistry and Molecular Biology,College of Life Sciences,Nankai University,Tianjin,300071,China

出　　处：《Acta Pharmacologica Sinica》2024年第11期2405-2419,共15页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82072943,China);the National Natural Science Foundation of China(82072929,China).

摘　　要：Poly(ADP-ribose)polymerase 1(PARP1)is a DNA-binding protein that is involved in various biological functions,including DNA damage repair and transcription regulation.It plays a crucial role in cisplatin resistance.Nevertheless,the exact regulatory pathways governing PARP1 have not yet been fully elucidated.In this study,we present evidence suggesting that the hepatitis B X-interacting protein(HBXIP)may exert regulatory control over PARP1.HBXIP functions as a transcriptional coactivator and is positively associated with PARP1 expression in tissues obtained from hepatoma patients in clinical settings,and its high expression promotes cisplatin resistance in hepatoma.We discovered that the oncogene HBXIP increases the level of PARP1 m6A modification by upregulating the RNA methyltransferase WTAP,leading to the accumulation of the PARP1 protein.In this process,on the one hand,HBXIP jointly activates the transcription factor ETV5,promoting the activation of the WTAP promoter and further facilitating the promotion of the m6A modification of PARP1 by WTAP methyltransferase,enhancing the RNA stability of PARP1.On the other hand,HBXIP can also jointly activate the transcription factor CEBPA,enhance the activity of the PARP1 promoter,and promote the upregulation of PARP1 expression,ultimately leading to enhanced DNA damage repair capability and promoting cisplatin resistance in hepatoma.Notably,aspirin inhibits HBXIP,thereby reducing the expression of PARP1.Overall,our research revealed a novel mechanism for increasing PARP1 abundance,and aspirin therapy could overcome cisplatin resistance in hepatoma.

关 键 词：HBXIP m^(6)A PARP1 cisplatin resistance HEPATOMA 

分 类 号：R735.7[医药卫生—肿瘤]