Suppression of Hepatocellular Carcinoma by Deletion of SIRT2 in Hepatocytes via Elevated C/EBPβ/GADD45γ.

IF 7.1 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Cellular and Molecular Gastroenterology and Hepatology Pub Date : 2025-03-11 DOI:10.1016/j.jcmgh.2025.101494
Fang Wang, Claudia Rose Keating, Yingchen Xu, Wei Hou, Greg Malnassy, Kyle Boedeker, Aldeb Perera, Eugene Ham, Diya Patel, Xianzhong Ding, Wei Qiu
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Abstract

Background & aims: There is a gap in our understanding of mechanisms promoting hepatocellular carcinoma (HCC), and this limits our ability to provide targeted therapy interventions for HCC. In HCC samples, NAD-dependent deacetylase sirtuin 2 (SIRT2) levels are increased and associated with a significantly worse prognosis, but the role of SIRT2 in hepatocarcinogenesis remains controversial.

Methods: To assess the role of SIRT2 in hepatocarcinogenesis, we used a hepatocyte-specific knockout of SIRT2 and two plasmid overexpression HCC models: MET/CAT and AKT/Nras. RNA-sequencing of mouse liver tissue was performed, and mechanistic findings were confirmed using IHC, qPCR, western blot, and CCK-8.

Results: Using the MET/CAT and AKT/Nras models, we found that SIRT2 is a significant mediator of liver tumorigenesis, with the knockout of SIRT2 delaying tumor growth. RNA-sequencing of MET/CAT-driven tumor tissue showed an increase in GADD45γ in SIRT2 knockout mice compared to WT. GADD45γ, or growth arrest and DNA-damage-inducible protein gamma, is a known tumor suppressor, but the regulation of GADD45γ by SIRT2 has not been shown. C/EBP proteins are known to regulate GADD45γ expression, and we found that C/EBPβ expression was increased in SIRT2 knockout livers and HCC cells. Also, C/EBPβ knockdown reversed GADD45γ expression and growth suppression following SIRT2 inhibition. Finally, C/EBPβ or GADD45γ overexpression significantly suppressed MET/CAT-induced HCC development.

Conclusions: SIRT2 is a potent tumor promotor in HCC that negatively regulates GADD45γ expression through C/EBPβ. The SIRT2-C/EBPβ-GADD45γ pathway elucidates a novel mechanism in HCC and establishes SIRT2 as a therapeutic target for HCC patients.

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肝细胞中 SIRT2 的缺失通过 C/EBPβ/GADD45γ 的升高抑制肝细胞癌。
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来源期刊
CiteScore
13.00
自引率
2.80%
发文量
246
审稿时长
42 days
期刊介绍: "Cell and Molecular Gastroenterology and Hepatology (CMGH)" is a journal dedicated to advancing the understanding of digestive biology through impactful research that spans the spectrum of normal gastrointestinal, hepatic, and pancreatic functions, as well as their pathologies. The journal's mission is to publish high-quality, hypothesis-driven studies that offer mechanistic novelty and are methodologically robust, covering a wide range of themes in gastroenterology, hepatology, and pancreatology. CMGH reports on the latest scientific advances in cell biology, immunology, physiology, microbiology, genetics, and neurobiology related to gastrointestinal, hepatobiliary, and pancreatic health and disease. The research published in CMGH is designed to address significant questions in the field, utilizing a variety of experimental approaches, including in vitro models, patient-derived tissues or cells, and animal models. This multifaceted approach enables the journal to contribute to both fundamental discoveries and their translation into clinical applications, ultimately aiming to improve patient care and treatment outcomes in digestive health.
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Suppression of Hepatocellular Carcinoma by Deletion of SIRT2 in Hepatocytes via Elevated C/EBPβ/GADD45γ. Inhibition of Ribosome Biogenesis in vivo Causes p53-Dependent Death and p53-Independent Dysfunction. Piezo1 specific deletion in macrophage protects the progression of chronic inflammatory bowel disease in mice. Cortactin facilitates malignant transformation of dysplastic cells in gastric cancer development. Attenuating ABHD17 isoforms augments the S-acylation and function of NOD2 and a subset of Crohn's disease-associated NOD2 variants.
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