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METTL5 stabilizes c‐Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in the world, with a high likelihood of metastasis and a dismal prognosis. The reprogramming of glucose metabolism is critical in the development of HCC. The Warburg effect has recently been confirmed to occur in a varie...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10009668/ https://www.ncbi.nlm.nih.gov/pubmed/36602428 http://dx.doi.org/10.1002/cac2.12403 |
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author | Xia, Peng Zhang, Hao Lu, Haofeng Xu, Kequan Jiang, Xiang Jiang, Yuke Gongye, Xiangdong Chen, Zhang Liu, Jie Chen, Xi Ma, Weijie Zhang, Zhonglin Yuan, Yufeng |
author_facet | Xia, Peng Zhang, Hao Lu, Haofeng Xu, Kequan Jiang, Xiang Jiang, Yuke Gongye, Xiangdong Chen, Zhang Liu, Jie Chen, Xi Ma, Weijie Zhang, Zhonglin Yuan, Yufeng |
author_sort | Xia, Peng |
collection | PubMed |
description | BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in the world, with a high likelihood of metastasis and a dismal prognosis. The reprogramming of glucose metabolism is critical in the development of HCC. The Warburg effect has recently been confirmed to occur in a variety of cancers, including HCC. However, little is known about the molecular biological mechanisms underlying the Warburg effect in HCC cells. In this study, we sought to better understand how methyltransferase 5, N6‐adenosine (METTL5) controls the development of HCC and the Warburg effect. METHODS: In the current study, quantitative real‐time polymerase chain reaction and Western blotting were used to detect the expression of METTL5 in HCC tissues and cell lines. Several different cell models and animal models were established to determine the role of METTL5 in glucose metabolism reprogramming and the underlying molecular mechanism of HCC. Glutathione‐S‐transferase pulldown, coimmunoprecipitation, RNA sequencing, non‐targeted metabolomics, polysome profiling, and luciferase reporter assays were performed to investigate the molecular mechanisms of METTL5 in HCC cells. RESULTS: We discovered that METTL5 drove glucose metabolic reprogramming to promote the proliferation and metastasis of HCC. Mechanistically, upregulation of METTL5 promoted c‐Myc stability and thus activated its downstream glycolytic genes lactate dehydrogenase A (LDHA), enolase 1 (ENO1), triosephosphate isomerase 1 (TPI1), solute carrier family 2 member 1 (SLC2A1), and pyruvate kinase M2 (PKM2). The c‐Box and ubiquitin binding domain (UBA) regions of ubiquitin specific peptidase 5 (USP5) binded to c‐Myc protein and inhibited K48‐linked polyubiquitination of c‐Myc. Further study revealed that METTL5 controled the USP5 translation process, which in turn regulated the ubiquitination of c‐Myc. Furthermore, we identified cAMP responsive element binding protein 1 (CREB1)/P300 as a critical transcriptional regulator of METTL5 that promoted the transcription of METTL5 in HCC. In patient‐derived tumor xenograft (PDX) models, adenovirus‐mediated knockout of METTL5 had a good antitumor effect and prolonged the survival of PDX‐bearing mice. CONCLUSIONS: These findings point to a novel mechanism by which CREB1/P300‐METTL5‐USP5‐c‐Myc controls abnormal glucose metabolism and promotes tumor growth, suggesting that METTL5 is a potential therapeutic target and prognostic biomarker for HCC. |
format | Online Article Text |
id | pubmed-10009668 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-100096682023-03-14 METTL5 stabilizes c‐Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression Xia, Peng Zhang, Hao Lu, Haofeng Xu, Kequan Jiang, Xiang Jiang, Yuke Gongye, Xiangdong Chen, Zhang Liu, Jie Chen, Xi Ma, Weijie Zhang, Zhonglin Yuan, Yufeng Cancer Commun (Lond) Original Articles BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in the world, with a high likelihood of metastasis and a dismal prognosis. The reprogramming of glucose metabolism is critical in the development of HCC. The Warburg effect has recently been confirmed to occur in a variety of cancers, including HCC. However, little is known about the molecular biological mechanisms underlying the Warburg effect in HCC cells. In this study, we sought to better understand how methyltransferase 5, N6‐adenosine (METTL5) controls the development of HCC and the Warburg effect. METHODS: In the current study, quantitative real‐time polymerase chain reaction and Western blotting were used to detect the expression of METTL5 in HCC tissues and cell lines. Several different cell models and animal models were established to determine the role of METTL5 in glucose metabolism reprogramming and the underlying molecular mechanism of HCC. Glutathione‐S‐transferase pulldown, coimmunoprecipitation, RNA sequencing, non‐targeted metabolomics, polysome profiling, and luciferase reporter assays were performed to investigate the molecular mechanisms of METTL5 in HCC cells. RESULTS: We discovered that METTL5 drove glucose metabolic reprogramming to promote the proliferation and metastasis of HCC. Mechanistically, upregulation of METTL5 promoted c‐Myc stability and thus activated its downstream glycolytic genes lactate dehydrogenase A (LDHA), enolase 1 (ENO1), triosephosphate isomerase 1 (TPI1), solute carrier family 2 member 1 (SLC2A1), and pyruvate kinase M2 (PKM2). The c‐Box and ubiquitin binding domain (UBA) regions of ubiquitin specific peptidase 5 (USP5) binded to c‐Myc protein and inhibited K48‐linked polyubiquitination of c‐Myc. Further study revealed that METTL5 controled the USP5 translation process, which in turn regulated the ubiquitination of c‐Myc. Furthermore, we identified cAMP responsive element binding protein 1 (CREB1)/P300 as a critical transcriptional regulator of METTL5 that promoted the transcription of METTL5 in HCC. In patient‐derived tumor xenograft (PDX) models, adenovirus‐mediated knockout of METTL5 had a good antitumor effect and prolonged the survival of PDX‐bearing mice. CONCLUSIONS: These findings point to a novel mechanism by which CREB1/P300‐METTL5‐USP5‐c‐Myc controls abnormal glucose metabolism and promotes tumor growth, suggesting that METTL5 is a potential therapeutic target and prognostic biomarker for HCC. John Wiley and Sons Inc. 2023-01-05 /pmc/articles/PMC10009668/ /pubmed/36602428 http://dx.doi.org/10.1002/cac2.12403 Text en © 2023 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat‐sen University Cancer Center. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Articles Xia, Peng Zhang, Hao Lu, Haofeng Xu, Kequan Jiang, Xiang Jiang, Yuke Gongye, Xiangdong Chen, Zhang Liu, Jie Chen, Xi Ma, Weijie Zhang, Zhonglin Yuan, Yufeng METTL5 stabilizes c‐Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression |
title | METTL5 stabilizes c‐Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression |
title_full | METTL5 stabilizes c‐Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression |
title_fullStr | METTL5 stabilizes c‐Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression |
title_full_unstemmed | METTL5 stabilizes c‐Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression |
title_short | METTL5 stabilizes c‐Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression |
title_sort | mettl5 stabilizes c‐myc by facilitating usp5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10009668/ https://www.ncbi.nlm.nih.gov/pubmed/36602428 http://dx.doi.org/10.1002/cac2.12403 |
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