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SMYD2 Promotes Hepatocellular Carcinoma Progression by Reprogramming Glutamine Metabolism via c-Myc/GLS1 Axis

Metabolic reprogramming, such as alterations in glutamine metabolism or glycolysis, is the hallmark of hepatocellular carcinoma (HCC). However, the underlying mechanisms are still incompletely elucidated. Previous studies have identified that methyltransferase SET and MYND domain-containing protein...

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Autores principales: Xu, Kangdi, Ding, Jun, Zhou, Lingfeng, Li, Dazhi, Luo, Jia, Wang, Wenchao, Shang, Mingge, Lin, Bingyi, Zhou, Lin, Zheng, Shusen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9818721/
https://www.ncbi.nlm.nih.gov/pubmed/36611819
http://dx.doi.org/10.3390/cells12010025
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author Xu, Kangdi
Ding, Jun
Zhou, Lingfeng
Li, Dazhi
Luo, Jia
Wang, Wenchao
Shang, Mingge
Lin, Bingyi
Zhou, Lin
Zheng, Shusen
author_facet Xu, Kangdi
Ding, Jun
Zhou, Lingfeng
Li, Dazhi
Luo, Jia
Wang, Wenchao
Shang, Mingge
Lin, Bingyi
Zhou, Lin
Zheng, Shusen
author_sort Xu, Kangdi
collection PubMed
description Metabolic reprogramming, such as alterations in glutamine metabolism or glycolysis, is the hallmark of hepatocellular carcinoma (HCC). However, the underlying mechanisms are still incompletely elucidated. Previous studies have identified that methyltransferase SET and MYND domain-containing protein 2(SMYD2) is responsible for the pathogenesis of numerous types of cancer. Here, we innovatively uncover how SMYD2 regulates glutamine metabolism in HCC cells and promotes HCC progression. We identified that SMYD2 expression is upregulated in HCC tissues, which correlates with unfavorable clinical outcomes. Our in vitro and in vivo results showed that the depletion of SMYD2 inhibits HCC cell growth. Mechanistically, c-Myc methylation by SMYD2 increases its protein stability through the ubiquitin–proteasome system. We showed SMYD2 depletion destabilized c-Myc protein by increasing the conjugated K48-linked polyubiquitin chain. SMYD2 increased c-Myc expression and further upregulated glutaminase1 (GLS1), a crucial enzyme that catalyzes the conversion of glutamine to glutamic acid, in HCC cells. GLS1 plays an important role in SMYD2-mediated HCC progression and glutamine metabolism regulation. The knockdown of SMYD2 inhibited glutamine metabolism in HCC cells and overcame their chemoresistance to sorafenib. Collectively, our findings demonstrated a novel mechanism of how SMYD2 promotes HCC progression by regulating glutamine metabolism through the c-Myc/GLS1signaling, implicating the therapeutic potential of targeting SMYD2 in HCC patients.
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spelling pubmed-98187212023-01-07 SMYD2 Promotes Hepatocellular Carcinoma Progression by Reprogramming Glutamine Metabolism via c-Myc/GLS1 Axis Xu, Kangdi Ding, Jun Zhou, Lingfeng Li, Dazhi Luo, Jia Wang, Wenchao Shang, Mingge Lin, Bingyi Zhou, Lin Zheng, Shusen Cells Article Metabolic reprogramming, such as alterations in glutamine metabolism or glycolysis, is the hallmark of hepatocellular carcinoma (HCC). However, the underlying mechanisms are still incompletely elucidated. Previous studies have identified that methyltransferase SET and MYND domain-containing protein 2(SMYD2) is responsible for the pathogenesis of numerous types of cancer. Here, we innovatively uncover how SMYD2 regulates glutamine metabolism in HCC cells and promotes HCC progression. We identified that SMYD2 expression is upregulated in HCC tissues, which correlates with unfavorable clinical outcomes. Our in vitro and in vivo results showed that the depletion of SMYD2 inhibits HCC cell growth. Mechanistically, c-Myc methylation by SMYD2 increases its protein stability through the ubiquitin–proteasome system. We showed SMYD2 depletion destabilized c-Myc protein by increasing the conjugated K48-linked polyubiquitin chain. SMYD2 increased c-Myc expression and further upregulated glutaminase1 (GLS1), a crucial enzyme that catalyzes the conversion of glutamine to glutamic acid, in HCC cells. GLS1 plays an important role in SMYD2-mediated HCC progression and glutamine metabolism regulation. The knockdown of SMYD2 inhibited glutamine metabolism in HCC cells and overcame their chemoresistance to sorafenib. Collectively, our findings demonstrated a novel mechanism of how SMYD2 promotes HCC progression by regulating glutamine metabolism through the c-Myc/GLS1signaling, implicating the therapeutic potential of targeting SMYD2 in HCC patients. MDPI 2022-12-21 /pmc/articles/PMC9818721/ /pubmed/36611819 http://dx.doi.org/10.3390/cells12010025 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Xu, Kangdi
Ding, Jun
Zhou, Lingfeng
Li, Dazhi
Luo, Jia
Wang, Wenchao
Shang, Mingge
Lin, Bingyi
Zhou, Lin
Zheng, Shusen
SMYD2 Promotes Hepatocellular Carcinoma Progression by Reprogramming Glutamine Metabolism via c-Myc/GLS1 Axis
title SMYD2 Promotes Hepatocellular Carcinoma Progression by Reprogramming Glutamine Metabolism via c-Myc/GLS1 Axis
title_full SMYD2 Promotes Hepatocellular Carcinoma Progression by Reprogramming Glutamine Metabolism via c-Myc/GLS1 Axis
title_fullStr SMYD2 Promotes Hepatocellular Carcinoma Progression by Reprogramming Glutamine Metabolism via c-Myc/GLS1 Axis
title_full_unstemmed SMYD2 Promotes Hepatocellular Carcinoma Progression by Reprogramming Glutamine Metabolism via c-Myc/GLS1 Axis
title_short SMYD2 Promotes Hepatocellular Carcinoma Progression by Reprogramming Glutamine Metabolism via c-Myc/GLS1 Axis
title_sort smyd2 promotes hepatocellular carcinoma progression by reprogramming glutamine metabolism via c-myc/gls1 axis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9818721/
https://www.ncbi.nlm.nih.gov/pubmed/36611819
http://dx.doi.org/10.3390/cells12010025
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