Gene amplification-driven RNA methyltransferase KIAA1429 promotes tumorigenesis by regulating BTG2 via m6A-YTHDF2-dependent in lung adenocarcinoma

Cancer Communications

article

Cheng Wang¹  Ni Li⁴  Guangfu Jin¹  Hongxia Ma¹  Zhibin Hu¹  Erbao Zhang¹  Fengwei Tan⁴  Hongbing Shen⁶  Chang Zhang⁶  Qi Sun¹  Xu Zhang¹  Na Qin¹  Zhening Pu⁸  Yayun Gu¹  Caiwang Yan¹  Meng Zhu¹  Juncheng Dai¹ 

[1] Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University;Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University;Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University;Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College;Gusu School, Nanjing Medical University;Department of Epidemiology, School of Public Health, Southeast University;Research Unit of Prospective Cohort of Cardiovascular Diseases and Cancers, Chinese Academy of Medical Sciences;Center of Clinical Research, Wuxi People's Hospital of Nanjing Medical University

关键词: BTG2;    gene amplification;    KIAA1429;    LUAD;    mRNA stability;    N6-methyladenosine;    RNA methyltransferase;    YTHDF2;   

DOI  :  10.1002/cac2.12325

学科分类：社会科学、人文和艺术（综合）

来源: Springer

【 摘 要 】

Background Epigenetic alterations have been shown to contribute immensely to human carcinogenesis. Dynamic and reversible N6-methyladenosine (m6A) RNA modification regulates gene expression and cell fate. However, the reasons for activation of KIAA1429 (also known as VIRMA, an RNA methyltransferase) and its underlying mechanism in lung adenocarcinoma (LUAD) remain largely unexplored. In this study, we aimed to clarify the oncogenic role of KIAA1429 in the tumorigenesis of LUAD. Methods Whole-genome sequencing and transcriptome sequencing of LUAD data were used to analyze the gene amplification of RNA methyltransferase. The in vitro and in vivo functions of KIAA1429 were investigated. Transcriptome sequencing, methylated RNA immunoprecipitation sequencing (MeRIP-seq), m6A dot blot assays and RNA immunoprecipitation (RIP) were performed to confirm the modified gene mediated by KIAA1429. RNA stability assays were used to detect the half-life of the target gene. Results Copy number amplification drove higher expression of KIAA1429 in LUAD, which was correlated with poor overall survival. Manipulating the expression of KIAA1429 could regulate the proliferation and metastasis of LUAD. Mechanistically, the target genes of KIAA1429-mediated m6A modification were confirmed by transcriptome sequencing and MeRIP-seq assays. We also revealed that KIAA1429 could regulate BTG2 expression in an m6A-dependent manner. Knockdown of KIAA1429 significantly decreased the m6A levels of BTG2 mRNA, leading to enhanced YTH m6A RNA binding protein 2 (YTHDF2, the m6A “reader”)-dependent BTG2 mRNA stability and promoted the expression of BTG2; thus, participating in the tumorigenesis of LUAD. Conclusions Our data revealed the activation mechanism and important role of KIAA1429 in LUAD tumorigenesis, which may provide a novel view on the targeted molecular therapy of LUAD.

【 授权许可】

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