m^(6)A-mediated regulation of PBX1-GCH1 axis promotes gastric cancer proliferation and metastasis by elevating tetrahydrobiopterin levels

作     者：Yinan Liu Ertao Zhai Junting Chen Yan Qian Risheng Zhao Yan Ma Jianqiu Liu Zhixin Huang Shirong Cai Jianhui Chen 

作者机构：Division of Gastrointestinal Surgery Centerthe First Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510080P.R.China Gastric Cancer CenterSun Yat-sen UniversityGuangzhouGuangdong 510080P.R.China Laboratory of Surgerythe First Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510080P.R.China 

出 版 物：《Cancer Communications》 (癌症通讯（英文）)

年 卷 期：2022年第42卷第4期

页      面：327-344页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：Natural Science Foundation of Guangdong Province,Grant/Award Numbers:2018A030313634,2020A1515010214,2021A1515010473 Guangdong Basic and Applied Basic Research Foundation,Grant/Award Numbers:2020A1515010214,2018A030313634,2021A1515010473 Young Teacher Foundation of Sun Yat-sen University,Grant/Award Number:19ykpy58 China Postdoctoral Science Foundation,Grant/Award Number:2020M683087 

主　　题：BH_(4) gastric cancer GCH1 m^(6)A metabolism reprogramming metastasis METTL3 PBX1 proliferation 

摘      要：Background:Methyltransferase 3(METTL3)-mediated N6-methyladenosine(m^(6)A)RNA modification has been demonstrated to be a potential factor in promoting gastric cancer(GC).METTL3 regulates a series of signaling pathways by modifying various *** study aimed to identify novel METTL3-mediated signaling pathways and explored possible targets for use in the clinical setting of gastric ***:To investigate the proliferation and metastatic capacity ofGCcell lines with METTL3 knockdown,a xenograft,lung metastasis,and popliteal lymph node metastasis model was ***^(6)A-modified RNA immunoprecipitation(Me-RIP)sequence was utilized to explore the target mRNAs of *** counting kit 8 and transwell assays were performed to investigate the promoting function of pre-B cell leukemia homeobox 1(PBX1)and GTP cyclohydrolase 1(GCH1).Western blotting and chromatin immunoprecipitation were employed to confirm the involvement of the METTL3-PBX1-GCH1 *** and liquid chromatography-mass spectrometry were used to explore the biological function of tetrahydrobiopterin(BH_(4)).Results:Knockdown of METTL3 suppressed xenograft tumor growth and lung/lymph node metastasis in ***,we found that METTL3 combined with and stabilized PBX1 *** immunoprecipitation(ChIP)and further experiments suggested that PBX1 acted as a transcription factor inducing GCH1 ***,the METTL3-PBX1-GCH1 axis increased BH_(4)levels in GC cells,thereby promoting tumor ***:This study suggested that METTL3 enzymes promote tumor growth and lung/lymph node metastasis via METTL3-PBX1-GCH1 axis increasing BH_(4)levels in GC.