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O-GlcNAc modified-TIP60/KAT5 is required for PCK1 deficiency-induced HCC metastasis
Aberrant glucose metabolism and elevated O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) are hallmarks of hepatocellular carcinoma (HCC). Loss of phosphoenolpyruvate carboxykinase 1 (PCK1), the major rate-limiting enzyme of hepatic gluconeogenesis, increases hexosamine biosynthetic pat...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8677624/ https://www.ncbi.nlm.nih.gov/pubmed/34650217 http://dx.doi.org/10.1038/s41388-021-02058-z |
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author | Liu, Rui Gou, Dongmei Xiang, Jin Pan, Xuanming Gao, Qingzhu Zhou, Peng Liu, Yi Hu, Jie Wang, Kai Tang, Ni |
author_facet | Liu, Rui Gou, Dongmei Xiang, Jin Pan, Xuanming Gao, Qingzhu Zhou, Peng Liu, Yi Hu, Jie Wang, Kai Tang, Ni |
author_sort | Liu, Rui |
collection | PubMed |
description | Aberrant glucose metabolism and elevated O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) are hallmarks of hepatocellular carcinoma (HCC). Loss of phosphoenolpyruvate carboxykinase 1 (PCK1), the major rate-limiting enzyme of hepatic gluconeogenesis, increases hexosamine biosynthetic pathway (HBP)-mediated protein O-GlcNAcylation in hepatoma cell and promotes cell growth and proliferation. However, whether PCK1 deficiency and hyper O-GlcNAcylation can induce HCC metastasis is largely unknown. Here, gain- and loss-of-function studies demonstrate that PCK1 suppresses HCC metastasis in vitro and in vivo. Specifically, lysine acetyltransferase 5 (KAT5), belonging to the MYST family of histone acetyltransferases (HAT), is highly modified by O-GlcNAcylation in PCK1 knockout hepatoma cells. Mechanistically, PCK1 depletion suppressed KAT5 ubiquitination by increasing its O-GlcNAcylation, thereby stabilizing KAT5. KAT5 O-GlcNAcylation epigenetically activates TWIST1 expression via histone H4 acetylation, and enhances MMP9 and MMP14 expression via c-Myc acetylation, thus promoting epithelial-mesenchymal transition (EMT) in HCC. In addition, targeting HBP-mediated O-GlcNAcylation of KAT5 inhibits lung metastasis of HCC in hepatospecific Pck1-deletion mice. Collectively, our findings demonstrate that PCK1 depletion increases O-GlcNAcylation of KAT5, epigenetically induces TWIST1 expression and promotes HCC metastasis, and link metabolic enzyme, post-translational modification (PTM) with epigenetic regulation. |
format | Online Article Text |
id | pubmed-8677624 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-86776242021-12-29 O-GlcNAc modified-TIP60/KAT5 is required for PCK1 deficiency-induced HCC metastasis Liu, Rui Gou, Dongmei Xiang, Jin Pan, Xuanming Gao, Qingzhu Zhou, Peng Liu, Yi Hu, Jie Wang, Kai Tang, Ni Oncogene Article Aberrant glucose metabolism and elevated O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) are hallmarks of hepatocellular carcinoma (HCC). Loss of phosphoenolpyruvate carboxykinase 1 (PCK1), the major rate-limiting enzyme of hepatic gluconeogenesis, increases hexosamine biosynthetic pathway (HBP)-mediated protein O-GlcNAcylation in hepatoma cell and promotes cell growth and proliferation. However, whether PCK1 deficiency and hyper O-GlcNAcylation can induce HCC metastasis is largely unknown. Here, gain- and loss-of-function studies demonstrate that PCK1 suppresses HCC metastasis in vitro and in vivo. Specifically, lysine acetyltransferase 5 (KAT5), belonging to the MYST family of histone acetyltransferases (HAT), is highly modified by O-GlcNAcylation in PCK1 knockout hepatoma cells. Mechanistically, PCK1 depletion suppressed KAT5 ubiquitination by increasing its O-GlcNAcylation, thereby stabilizing KAT5. KAT5 O-GlcNAcylation epigenetically activates TWIST1 expression via histone H4 acetylation, and enhances MMP9 and MMP14 expression via c-Myc acetylation, thus promoting epithelial-mesenchymal transition (EMT) in HCC. In addition, targeting HBP-mediated O-GlcNAcylation of KAT5 inhibits lung metastasis of HCC in hepatospecific Pck1-deletion mice. Collectively, our findings demonstrate that PCK1 depletion increases O-GlcNAcylation of KAT5, epigenetically induces TWIST1 expression and promotes HCC metastasis, and link metabolic enzyme, post-translational modification (PTM) with epigenetic regulation. Nature Publishing Group UK 2021-10-14 2021 /pmc/articles/PMC8677624/ /pubmed/34650217 http://dx.doi.org/10.1038/s41388-021-02058-z Text en © The Author(s) 2021 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Liu, Rui Gou, Dongmei Xiang, Jin Pan, Xuanming Gao, Qingzhu Zhou, Peng Liu, Yi Hu, Jie Wang, Kai Tang, Ni O-GlcNAc modified-TIP60/KAT5 is required for PCK1 deficiency-induced HCC metastasis |
title | O-GlcNAc modified-TIP60/KAT5 is required for PCK1 deficiency-induced HCC metastasis |
title_full | O-GlcNAc modified-TIP60/KAT5 is required for PCK1 deficiency-induced HCC metastasis |
title_fullStr | O-GlcNAc modified-TIP60/KAT5 is required for PCK1 deficiency-induced HCC metastasis |
title_full_unstemmed | O-GlcNAc modified-TIP60/KAT5 is required for PCK1 deficiency-induced HCC metastasis |
title_short | O-GlcNAc modified-TIP60/KAT5 is required for PCK1 deficiency-induced HCC metastasis |
title_sort | o-glcnac modified-tip60/kat5 is required for pck1 deficiency-induced hcc metastasis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8677624/ https://www.ncbi.nlm.nih.gov/pubmed/34650217 http://dx.doi.org/10.1038/s41388-021-02058-z |
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