N6-methyladenosine reader IMP2 stabilizes the ZFAS1/OLA1 axis and activates the Warburg effect: implication in colorectal cancer

Journal of Hematology & Oncology

Yalun Li¹  Senxu Lu²  Huizhe Wu²  Li Han²  Miao He²  Qiuchen Chen²  Xiaoyun Hu²  Dongping Xu²  Tong Sun²  Weifan Yao³  Minjie Wei³  Zhenning Wang⁴ 

[1] Department of Anorectal Surgery, First Affiliated Hospital of China Medical University, 110001, Shenyang, People’s Republic of China;Department of Pharmacology, School of Pharmacy, China Medical University, 110122, Shenyang, People’s Republic of China;Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation; Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education; China Medical University, 110122, Shenyang, People’s Republic of China;Department of Pharmacology, School of Pharmacy, China Medical University, 110122, Shenyang, People’s Republic of China;Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation; Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education; China Medical University, 110122, Shenyang, People’s Republic of China;Shenyang Kangwei Medical Laboratory Analysis Co. LTD, Shenyang, Liaoning Province, People’s Republic of China;Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, First Affiliated Hospital of China Medical University, 110001, Shenyang, People’s Republic of China;

关键词: mA methylation;    IMP2;    ATP-hydrolyzing and glycolysis;    ZFAS1;    OLA1;    Colorectal cancer;   

DOI  :  10.1186/s13045-021-01204-0

来源: Springer

【 摘 要 】

BackgroundAccumulating evidence shows that N6-methyladenine (m6A) modulators contribute to the etiology and progression of colorectal cancer (CRC). However, the exact mechanisms of m6A reader involved in glycolytic metabolism remain vague. This article aimed to crosstalk the m6A reader with glycolytic metabolism and reveal a new mechanism for the progression of CRC.MethodsThe relationship between candidate lncRNA and m6A reader was analyzed by bioinformatics, ISH and IHC assays. In vivo and in vitro studies (including MTT, CFA, trans-well, apoptosis, western blot, qRT-PCR and xenograft mouse models) were utilized to explore the biological functions of these indicators. Lactate detection, ATP activity detection and ECAR assays were used to verify the biological function of the downstream target. The bioinformatics, RNA stability, RIP experiments and RNA pull-down assays were used to explore the potential molecular mechanisms.ResultsWe identified that the crosstalk of the m6A reader IMP2 with long-noncoding RNA (lncRNA) ZFAS1 in an m6A modulation-dependent manner, subsequently augmented the recruitment of Obg-like ATPase 1 (OLA1) and adenosine triphosphate (ATP) hydrolysis and glycolysis during CRC proliferation and progression. Specifically, IMP2 and ZFAS1 are significantly overexpressed with elevated m6A levels in CRC cells and paired CRC cohorts (n = 144). These indicators could be independent biomarkers for CRC prognostic prediction. Notably, IMP2 regulated ZFAS1 expression and enhanced CRC cell proliferation, colony formation, and apoptosis inhibition; thus, it was oncogenic. Mechanistically, ZFAS1 is modified at adenosine +843 within the RGGAC/RRACH element in an m6A-dependent manner. Thus, direct interaction between the KH3–4 domain of IMP2 and ZFAS1 where IMP2 serves as a reader for m6A-modified ZFAS1 and promotes the RNA stability of ZFAS1 is critical for CRC development. More importantly, stabilized ZFAS1 recognizes the OBG-type functional domain of OLA1, which facilitated the exposure of ATP-binding sites (NVGKST, 32–37), enhanced its protein activity, and ultimately accelerated ATP hydrolysis and the Warburg effect.ConclusionsOur findings reveal a new cancer-promoting mechanism, that is, the critical modulation network underlying m6A readers stabilizes lncRNAs, and they jointly promote mitochondrial energy metabolism in the pathogenesis of CRC.

【 授权许可】

CC BY