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HMGCS2 Mediates Ketone Production and Regulates the Proliferation and Metastasis of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor worldwide; however, the traditional therapeutic approaches and survival rates are still limited. To improve current therapies, it is necessary to investigate the molecular mechanisms underlying liver cancer and to identify pot...

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Autores principales: Wang, Yuan-Hsi, Liu, Chao-Lien, Chiu, Wan-Chun, Twu, Yuh-Ching, Liao, Yi-Jen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966636/
https://www.ncbi.nlm.nih.gov/pubmed/31779269
http://dx.doi.org/10.3390/cancers11121876
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author Wang, Yuan-Hsi
Liu, Chao-Lien
Chiu, Wan-Chun
Twu, Yuh-Ching
Liao, Yi-Jen
author_facet Wang, Yuan-Hsi
Liu, Chao-Lien
Chiu, Wan-Chun
Twu, Yuh-Ching
Liao, Yi-Jen
author_sort Wang, Yuan-Hsi
collection PubMed
description Hepatocellular carcinoma (HCC) is the most common primary malignant tumor worldwide; however, the traditional therapeutic approaches and survival rates are still limited. To improve current therapies, it is necessary to investigate the molecular mechanisms underlying liver cancer and to identify potential therapeutic targets. The aims of this study were to verify the mechanisms and therapeutic potential of the ketogenesis rate-limiting enzyme 3-Hydroxymethylglutaryl-CoA synthase 2 (HMGCS2) in HCC. Immunohistochemical staining of human liver disease tissue arrays showed that HMGCS2 is abundantly expressed in normal liver tissues but is downregulated in cirrhosis and HCC tissues. In HCC patients, lower HMGCS2 expression was correlated with higher pathological grades and clinical stages. In our investigation of the molecular mechanisms of HMGCS2 in HCC, we showed that knockdown of HMGCS2 decreased ketone production, which promoted cell proliferation, cell migration, and xenograft tumorigenesis by enhancing c-Myc/cyclinD1 and EMT signaling and by suppressing the caspase-dependent apoptosis pathway. Ketone body treatment reduced the proliferation- and migration-promoting effects of HMGCS2 knockdown in cells. In contrast, HMGCS2 overexpression increased the intracellular ketone level and inhibited cell proliferation, cell migration, and xenograft tumorigenesis. Finally, ketogenic diet administration significantly inhibited liver cancer cell growth in mice. Our studies highlight the potential therapeutic strategy of targeting HMGCS2-mediated ketogenesis in liver cancer.
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spelling pubmed-69666362020-02-04 HMGCS2 Mediates Ketone Production and Regulates the Proliferation and Metastasis of Hepatocellular Carcinoma Wang, Yuan-Hsi Liu, Chao-Lien Chiu, Wan-Chun Twu, Yuh-Ching Liao, Yi-Jen Cancers (Basel) Article Hepatocellular carcinoma (HCC) is the most common primary malignant tumor worldwide; however, the traditional therapeutic approaches and survival rates are still limited. To improve current therapies, it is necessary to investigate the molecular mechanisms underlying liver cancer and to identify potential therapeutic targets. The aims of this study were to verify the mechanisms and therapeutic potential of the ketogenesis rate-limiting enzyme 3-Hydroxymethylglutaryl-CoA synthase 2 (HMGCS2) in HCC. Immunohistochemical staining of human liver disease tissue arrays showed that HMGCS2 is abundantly expressed in normal liver tissues but is downregulated in cirrhosis and HCC tissues. In HCC patients, lower HMGCS2 expression was correlated with higher pathological grades and clinical stages. In our investigation of the molecular mechanisms of HMGCS2 in HCC, we showed that knockdown of HMGCS2 decreased ketone production, which promoted cell proliferation, cell migration, and xenograft tumorigenesis by enhancing c-Myc/cyclinD1 and EMT signaling and by suppressing the caspase-dependent apoptosis pathway. Ketone body treatment reduced the proliferation- and migration-promoting effects of HMGCS2 knockdown in cells. In contrast, HMGCS2 overexpression increased the intracellular ketone level and inhibited cell proliferation, cell migration, and xenograft tumorigenesis. Finally, ketogenic diet administration significantly inhibited liver cancer cell growth in mice. Our studies highlight the potential therapeutic strategy of targeting HMGCS2-mediated ketogenesis in liver cancer. MDPI 2019-11-26 /pmc/articles/PMC6966636/ /pubmed/31779269 http://dx.doi.org/10.3390/cancers11121876 Text en © 2019 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wang, Yuan-Hsi
Liu, Chao-Lien
Chiu, Wan-Chun
Twu, Yuh-Ching
Liao, Yi-Jen
HMGCS2 Mediates Ketone Production and Regulates the Proliferation and Metastasis of Hepatocellular Carcinoma
title HMGCS2 Mediates Ketone Production and Regulates the Proliferation and Metastasis of Hepatocellular Carcinoma
title_full HMGCS2 Mediates Ketone Production and Regulates the Proliferation and Metastasis of Hepatocellular Carcinoma
title_fullStr HMGCS2 Mediates Ketone Production and Regulates the Proliferation and Metastasis of Hepatocellular Carcinoma
title_full_unstemmed HMGCS2 Mediates Ketone Production and Regulates the Proliferation and Metastasis of Hepatocellular Carcinoma
title_short HMGCS2 Mediates Ketone Production and Regulates the Proliferation and Metastasis of Hepatocellular Carcinoma
title_sort hmgcs2 mediates ketone production and regulates the proliferation and metastasis of hepatocellular carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966636/
https://www.ncbi.nlm.nih.gov/pubmed/31779269
http://dx.doi.org/10.3390/cancers11121876
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