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

Abstract Background Accumulating 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 wit...

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Autores principales:	Senxu Lu, Li Han, Xiaoyun Hu, Tong Sun, Dongping Xu, Yalun Li, Qiuchen Chen, Weifan Yao, Miao He, Zhenning Wang, Huizhe Wu, Minjie Wei
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	m6A methylation IMP2 ATP-hydrolyzing and glycolysis ZFAS1 OLA1 Colorectal cancer Diseases of the blood and blood-forming organs RC633-647.5 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/4e1217b06a014e1caa21783e01cca7fd
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spelling	oai:doaj.org-article:4e1217b06a014e1caa21783e01cca7fd2021-11-14T12:05:42ZN6-methyladenosine reader IMP2 stabilizes the ZFAS1/OLA1 axis and activates the Warburg effect: implication in colorectal cancer10.1186/s13045-021-01204-01756-8722https://doaj.org/article/4e1217b06a014e1caa21783e01cca7fd2021-11-01T00:00:00Zhttps://doi.org/10.1186/s13045-021-01204-0https://doaj.org/toc/1756-8722Abstract Background Accumulating 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. Methods The 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. Results We 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. Conclusions Our 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.Senxu LuLi HanXiaoyun HuTong SunDongping XuYalun LiQiuchen ChenWeifan YaoMiao HeZhenning WangHuizhe WuMinjie WeiBMCarticlem6A methylationIMP2ATP-hydrolyzing and glycolysisZFAS1OLA1Colorectal cancerDiseases of the blood and blood-forming organsRC633-647.5Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal of Hematology & Oncology, Vol 14, Iss 1, Pp 1-23 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	m6A methylation IMP2 ATP-hydrolyzing and glycolysis ZFAS1 OLA1 Colorectal cancer Diseases of the blood and blood-forming organs RC633-647.5 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	m6A methylation IMP2 ATP-hydrolyzing and glycolysis ZFAS1 OLA1 Colorectal cancer Diseases of the blood and blood-forming organs RC633-647.5 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Senxu Lu Li Han Xiaoyun Hu Tong Sun Dongping Xu Yalun Li Qiuchen Chen Weifan Yao Miao He Zhenning Wang Huizhe Wu Minjie Wei N6-methyladenosine reader IMP2 stabilizes the ZFAS1/OLA1 axis and activates the Warburg effect: implication in colorectal cancer
description	Abstract Background Accumulating 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. Methods The 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. Results We 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. Conclusions Our 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.
format	article
author	Senxu Lu Li Han Xiaoyun Hu Tong Sun Dongping Xu Yalun Li Qiuchen Chen Weifan Yao Miao He Zhenning Wang Huizhe Wu Minjie Wei
author_facet	Senxu Lu Li Han Xiaoyun Hu Tong Sun Dongping Xu Yalun Li Qiuchen Chen Weifan Yao Miao He Zhenning Wang Huizhe Wu Minjie Wei
author_sort	Senxu Lu
title	N6-methyladenosine reader IMP2 stabilizes the ZFAS1/OLA1 axis and activates the Warburg effect: implication in colorectal cancer
title_short	N6-methyladenosine reader IMP2 stabilizes the ZFAS1/OLA1 axis and activates the Warburg effect: implication in colorectal cancer
title_full	N6-methyladenosine reader IMP2 stabilizes the ZFAS1/OLA1 axis and activates the Warburg effect: implication in colorectal cancer
title_fullStr	N6-methyladenosine reader IMP2 stabilizes the ZFAS1/OLA1 axis and activates the Warburg effect: implication in colorectal cancer
title_full_unstemmed	N6-methyladenosine reader IMP2 stabilizes the ZFAS1/OLA1 axis and activates the Warburg effect: implication in colorectal cancer
title_sort	n6-methyladenosine reader imp2 stabilizes the zfas1/ola1 axis and activates the warburg effect: implication in colorectal cancer
publisher	BMC
publishDate	2021
url	https://doaj.org/article/4e1217b06a014e1caa21783e01cca7fd
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N6-methyladenosine reader IMP2 stabilizes the ZFAS1/OLA1 axis and activates the Warburg effect: implication in colorectal cancer

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