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LncRNA FTO-IT1 promotes glycolysis and progression of hepatocellular carcinoma through modulating FTO-mediated N6-methyladenosine modification on GLUT1 and PKM2

BACKGROUND: Long non-coding RNAs (LncRNAs) have been extensively studied to play essential roles in tumor progression. However, more in-depth studies are waiting to be solved on how lncRNAs regulate the progression of hepatocellular carcinoma (HCC). METHODS: Different expression levels of lncRNAs in...

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Autores principales: Wang, Fan, Hu, Yuhang, Wang, Hongda, Hu, Ping, Xiong, Hewei, Zeng, Zhu, Han, Shengbo, Wang, Decai, Wang, Jie, Zhao, Yong, Huang, Yan, Zhuo, Wenfeng, Lv, Guozheng, Zhao, Gang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578010/
https://www.ncbi.nlm.nih.gov/pubmed/37840133
http://dx.doi.org/10.1186/s13046-023-02847-2
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author Wang, Fan
Hu, Yuhang
Wang, Hongda
Hu, Ping
Xiong, Hewei
Zeng, Zhu
Han, Shengbo
Wang, Decai
Wang, Jie
Zhao, Yong
Huang, Yan
Zhuo, Wenfeng
Lv, Guozheng
Zhao, Gang
author_facet Wang, Fan
Hu, Yuhang
Wang, Hongda
Hu, Ping
Xiong, Hewei
Zeng, Zhu
Han, Shengbo
Wang, Decai
Wang, Jie
Zhao, Yong
Huang, Yan
Zhuo, Wenfeng
Lv, Guozheng
Zhao, Gang
author_sort Wang, Fan
collection PubMed
description BACKGROUND: Long non-coding RNAs (LncRNAs) have been extensively studied to play essential roles in tumor progression. However, more in-depth studies are waiting to be solved on how lncRNAs regulate the progression of hepatocellular carcinoma (HCC). METHODS: Different expression levels of lncRNAs in HCC cells were compared by analysis of Gene Expression Omnibus and The Cancer Genome Atlas databases. The effects of lncRNA FTO Intronic Transcript 1 (FTO-IT1) on HCC cells were assessed by gain- and loss-of-function experiments. Colony formation assay, Edu assay, glucose uptake and lactic acid production assay were performed to evaluate the regulation of proliferation and glycolysis of HCC cells by FTO-IT1. The binding between protein interleukin enhancer binding factor 2/3 (ILF2/ILF3) and FTO-IT1 was determined by RNA pull-down, mass spectroscopy and RNA immunoprecipitation experiments. RNA stability assay, quantitative reverse transcription PCR and Western blot were employed to determine the regulatory mechanisms of FTO-IT1 on fat mass and obesity-associated (FTO). Methylated RNA immunoprecipitation assay was used to assessed the regulation of key enzymes of glycolysis by FTO. The role of FTO-IT1/FTO in vivo was confirmed via xenograft tumor model. RESULTS: LncRNA FTO-IT1, an intronic region transcript of FTO gene, was highly expressed in HCC and associated with poor prognosis of patients with HCC. FTO-IT1 was related to proliferation and glycolysis of HCC cells, and contributed to the malignant progression of HCC by promoting glycolysis. Mechanistically, FTO-IT1 induced stabilization of FTO mRNA by recruiting ILF2/ILF3 protein complex to 3’UTR of FTO mRNA. As a demethylase for N(6)-methyladenosine (m(6)A), FTO decreased m(6)A modification on mRNAs of glycolysis associated genes including GLUT1, PKM2, and c-Myc which alleviated the YTH N6-methyladenosine RNA binding protein 2 (YTHDF2)-mediated mRNA degradation. Therefore, the upregulated expression of FTO-IT1 leaded to overexpression of GLUT1, PKM2, and c-Myc by which enhanced glycolysis of HCC. Meanwhile, it was found that c-Myc transcriptional regulated expression of FTO-IT1 by binding to its promoter area under hypo-glucose condition, forming a reciprocal loop between c-Myc and FTO-IT1. CONCLUSIONS: This study identified an important role of the FTO-IT1/FTO axis mediated m(6)A modification of glycolytic genes contributed to glycolysis and tumorigenesis of HCC, and FTO-IT1 might be served as a new therapeutic target for HCC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-023-02847-2.
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spelling pubmed-105780102023-10-17 LncRNA FTO-IT1 promotes glycolysis and progression of hepatocellular carcinoma through modulating FTO-mediated N6-methyladenosine modification on GLUT1 and PKM2 Wang, Fan Hu, Yuhang Wang, Hongda Hu, Ping Xiong, Hewei Zeng, Zhu Han, Shengbo Wang, Decai Wang, Jie Zhao, Yong Huang, Yan Zhuo, Wenfeng Lv, Guozheng Zhao, Gang J Exp Clin Cancer Res Research BACKGROUND: Long non-coding RNAs (LncRNAs) have been extensively studied to play essential roles in tumor progression. However, more in-depth studies are waiting to be solved on how lncRNAs regulate the progression of hepatocellular carcinoma (HCC). METHODS: Different expression levels of lncRNAs in HCC cells were compared by analysis of Gene Expression Omnibus and The Cancer Genome Atlas databases. The effects of lncRNA FTO Intronic Transcript 1 (FTO-IT1) on HCC cells were assessed by gain- and loss-of-function experiments. Colony formation assay, Edu assay, glucose uptake and lactic acid production assay were performed to evaluate the regulation of proliferation and glycolysis of HCC cells by FTO-IT1. The binding between protein interleukin enhancer binding factor 2/3 (ILF2/ILF3) and FTO-IT1 was determined by RNA pull-down, mass spectroscopy and RNA immunoprecipitation experiments. RNA stability assay, quantitative reverse transcription PCR and Western blot were employed to determine the regulatory mechanisms of FTO-IT1 on fat mass and obesity-associated (FTO). Methylated RNA immunoprecipitation assay was used to assessed the regulation of key enzymes of glycolysis by FTO. The role of FTO-IT1/FTO in vivo was confirmed via xenograft tumor model. RESULTS: LncRNA FTO-IT1, an intronic region transcript of FTO gene, was highly expressed in HCC and associated with poor prognosis of patients with HCC. FTO-IT1 was related to proliferation and glycolysis of HCC cells, and contributed to the malignant progression of HCC by promoting glycolysis. Mechanistically, FTO-IT1 induced stabilization of FTO mRNA by recruiting ILF2/ILF3 protein complex to 3’UTR of FTO mRNA. As a demethylase for N(6)-methyladenosine (m(6)A), FTO decreased m(6)A modification on mRNAs of glycolysis associated genes including GLUT1, PKM2, and c-Myc which alleviated the YTH N6-methyladenosine RNA binding protein 2 (YTHDF2)-mediated mRNA degradation. Therefore, the upregulated expression of FTO-IT1 leaded to overexpression of GLUT1, PKM2, and c-Myc by which enhanced glycolysis of HCC. Meanwhile, it was found that c-Myc transcriptional regulated expression of FTO-IT1 by binding to its promoter area under hypo-glucose condition, forming a reciprocal loop between c-Myc and FTO-IT1. CONCLUSIONS: This study identified an important role of the FTO-IT1/FTO axis mediated m(6)A modification of glycolytic genes contributed to glycolysis and tumorigenesis of HCC, and FTO-IT1 might be served as a new therapeutic target for HCC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-023-02847-2. BioMed Central 2023-10-16 /pmc/articles/PMC10578010/ /pubmed/37840133 http://dx.doi.org/10.1186/s13046-023-02847-2 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Wang, Fan
Hu, Yuhang
Wang, Hongda
Hu, Ping
Xiong, Hewei
Zeng, Zhu
Han, Shengbo
Wang, Decai
Wang, Jie
Zhao, Yong
Huang, Yan
Zhuo, Wenfeng
Lv, Guozheng
Zhao, Gang
LncRNA FTO-IT1 promotes glycolysis and progression of hepatocellular carcinoma through modulating FTO-mediated N6-methyladenosine modification on GLUT1 and PKM2
title LncRNA FTO-IT1 promotes glycolysis and progression of hepatocellular carcinoma through modulating FTO-mediated N6-methyladenosine modification on GLUT1 and PKM2
title_full LncRNA FTO-IT1 promotes glycolysis and progression of hepatocellular carcinoma through modulating FTO-mediated N6-methyladenosine modification on GLUT1 and PKM2
title_fullStr LncRNA FTO-IT1 promotes glycolysis and progression of hepatocellular carcinoma through modulating FTO-mediated N6-methyladenosine modification on GLUT1 and PKM2
title_full_unstemmed LncRNA FTO-IT1 promotes glycolysis and progression of hepatocellular carcinoma through modulating FTO-mediated N6-methyladenosine modification on GLUT1 and PKM2
title_short LncRNA FTO-IT1 promotes glycolysis and progression of hepatocellular carcinoma through modulating FTO-mediated N6-methyladenosine modification on GLUT1 and PKM2
title_sort lncrna fto-it1 promotes glycolysis and progression of hepatocellular carcinoma through modulating fto-mediated n6-methyladenosine modification on glut1 and pkm2
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578010/
https://www.ncbi.nlm.nih.gov/pubmed/37840133
http://dx.doi.org/10.1186/s13046-023-02847-2
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