Inhibiting histone deacetylases suppresses glucose metabolism and hepatocellular carcinoma growth by restoring FBP1 expression

Background: Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide and establishment of new chemotherapies for HCC is urgently needed. GPR41 [free fatty acid receptor 3 (FFA3)] is a G protein-coupled receptor for short chain fatty acids, including acetate, propionate, and butyrate. In our previous study, we showed that propionate enhances the cytotoxic effect of cisplatin in HCC cells and that this mechanism is dependent on inhibition of histone deacetylases (HDACs) via GPR41/FFA3. However, the antitumor action of GPR41/FFA3 has not been elucidated. Methods: In this study, we examined AR420626 as a GPR41-selective agonist in HepG2 and HLE cells. Nude mice were used for HepG2 xenograft studies. The apoptotic effect of AR420626 was evaluated using flow cytometry analysis. Expression of apoptosis-related proteins and HDACs was evaluated by Western immunoblot. Gene silencing of HDAC 3/5/7 and GPR41 was performed using small interfering RNA. Expression of TNF-α mRNA was evaluated by TaqMan real-time polymerase chain reaction. Results: We found that AR420626, a selective GPR41/FFA3 agonist, suppressed growth of HepG2 xenografts and inhibited proliferation of HCC cells by inducing apoptosis. AR420626 induced proteasome activation through mTOR phosphorylation, which reduced HDAC proteins, and then increased expression of TNF-α. Conclusion: AR420626, a selective GPR41/FFA3 agonist, may be a candidate as a therapeutic agent for HCC.

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HDAC9 Is Preferentially Expressed in Dedifferentiated Hepatocellular Carcinoma Cells and Is Involved in an Anchorage-Independent Growth

Cancers ◽

10.3390/cancers12102734 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2734

Author(s):

Keita Kanki ◽

Ryota Watanabe ◽

Le Nguyen Thai ◽

Chun-Hao Zhao ◽

Kyoko Naito

Keyword(s):

Hepatocellular Carcinoma ◽

Histone Deacetylases ◽

Epithelial Mesenchymal Transition ◽

Cell Transformation ◽

The Cancer Genome Atlas ◽

Hepatic Differentiation ◽

Differentiation Markers ◽

Mesenchymal Transition ◽

Cancer Genome Atlas ◽

Hcc Cells

Aberrant activation of histone deacetylases (HDACs) is one of the causes of tumor cell transformation in many types of cancer, however, the critical HDAC responsible for the malignant transformation remain unclear. To identify the HDAC related to the dedifferentiation of hepatocellular carcinoma (HCC) cells, we investigated the expression profile of HDACs in differentiated and undifferentiated hepatoma cells. We found that HDAC9, a member of the class II HDAC, is preferentially expressed in undifferentiated HCC cells. Analysis of 373 HCC patients in The Cancer Genome Atlas (TCGA) database revealed that the expression of HDAC9 mRNA positively correlated with the markers of mesenchymal phenotype and stemness, and conversely, negatively correlated with hepatic differentiation markers. HDAC9 was transcriptionally upregulated in epithelial–mesenchymal transition (EMT)-induced HCC cells treated with TGF-β. Genetic and pharmacological inhibition of HDAC9 in undifferentiated HCC cells showed decreased sphere-forming activity, which indicates an ability of anchorage-independent cell growth and self-renewal. We also showed that aldehyde dehydrogenase 1A3 (ALDH1A3) was downregulated in HDAC9-suppressing cells, and ALDH inhibitor disulfiram significantly decreased the sphere formation of undifferentiated HCC cells. Together, our data provide useful information for the development of HDAC9-specific inhibitors for the treatment of HCC progression.

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Nur77 suppresses hepatocellular carcinoma via switching glucose metabolism toward gluconeogenesis through attenuating phosphoenolpyruvate carboxykinase sumoylation

Nature Communications ◽

10.1038/ncomms14420 ◽

2017 ◽

Vol 8 (1) ◽

Cited By ~ 31

Author(s):

Xue-li Bian ◽

Hang-zi Chen ◽

Peng-bo Yang ◽

Ying-ping Li ◽

Fen-na Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Glucose Metabolism ◽

Phosphoenolpyruvate Carboxykinase

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Histone deacetylase 5 regulates glucose uptake and insulin action in muscle cells

Journal of Molecular Endocrinology ◽

10.1530/jme-12-0095 ◽

2012 ◽

Vol 49 (3) ◽

pp. 203-211 ◽

Cited By ~ 29

Author(s):

Suryaprakash Raichur ◽

Song Hooi Teh ◽

Kenji Ohwaki ◽

Vidhi Gaur ◽

Yun Chau Long ◽

...

Keyword(s):

Glucose Metabolism ◽

Glucose Uptake ◽

Histone Deacetylases ◽

Insulin Action ◽

Metabolic Flux ◽

Muscle Development ◽

Glycogen Synthesis ◽

Hdac Inhibitors ◽

Muscle Cells ◽

Histone Deacetylation

The class IIa histone deacetylases (HDACs) act as transcriptional repressors by altering chromatin structure through histone deacetylation. This family of enzymes regulates muscle development and phenotype, through regulation of muscle-specific genes including myogenin and MyoD (MYOD1). More recently, class IIa HDACs have been implicated in regulation of genes involved in glucose metabolism. However, the effects of HDAC5 on glucose metabolism and insulin action have not been directly assessed. Knockdown of HDAC5 in human primary muscle cells increased glucose uptake and was associated with increased GLUT4 (SLC2A4) expression and promoter activity but was associated with reduced GLUT1 (SLC2A1) expression. There was no change in PGC-1α (PPARGC1A) expression. The effects of HDAC5 knockdown on glucose metabolism were not due to alterations in the initiation of differentiation, as knockdown of HDAC5 after the onset of differentiation also resulted in increased glucose uptake and insulin-stimulated glycogen synthesis. These data show that inhibition of HDAC5 enhances metabolism and insulin action in muscle cells. As these processes in muscle are dysregulated in metabolic disease, HDAC inhibition could be an effective therapeutic strategy to improve muscle metabolism in these diseases. Therefore, we also examined the effects of the pan HDAC inhibitor, Scriptaid, on muscle cell metabolism. In myotubes, Scriptaid increased histone 3 acetylation, GLUT4 expression, glucose uptake and both oxidative and non-oxidative metabolic flux. Together, these data suggest that HDAC5 regulates muscle glucose metabolism and insulin action and that HDAC inhibitors can be used to modulate these parameters in muscle cells.

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Hepatitis C virus core protein interacts with Snail and histone deacetylases to promote the metastasis of hepatocellular carcinoma

Oncogene ◽

10.1038/onc.2015.428 ◽

2015 ◽

Vol 35 (28) ◽

pp. 3626-3635 ◽

Cited By ~ 16

Author(s):

D Nie ◽

X Shan ◽

L Nie ◽

Y Duan ◽

Z Chen ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Histone Deacetylases ◽

Core Protein ◽

Virus Core

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MiR-130a-3p Regulates the Glycolysis via Targeting PDK1 in Hepatocellular Carcinoma

10.21203/rs.3.rs-1155969/v1 ◽

2021 ◽

Author(s):

Hai-Long Li ◽

Jie Shi ◽

Qi Qi ◽

Yue Huang ◽

Chi Liu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Glucose Metabolism ◽

Pyruvate Dehydrogenase ◽

Pyruvate Dehydrogenase Kinase ◽

Luciferase Reporter ◽

Luciferase Reporter Gene ◽

And Migration ◽

Low Expression ◽

Hcc Cells

Abstract MiR-130a-3p has been certified to have low expression in several types of tumors. However, the function of miR-130a-3p in glucose metabolism and hepatocellular carcinoma progression is still elusive. Here we report that miR-130a-3p has explicitly low expression in human HCC tissues and cells and is closely related to the patient's tumor size and grade. Overexpression of miR-130a-3p significantly inhibits the glucose metabolism, proliferation and migration of HCC cells in vitro. In order to further study the effects of miR-130a-3p in the glucose metabolism of HCC cells, we found that overexpression of miR-130a-3p significantly inhibited the expression of pyruvate dehydrogenase kinase 1 (PDK1). Consistently, we confirmed that PDK1 is the target gene of miR-130a-3p through dual luciferase reporter gene assays. Cell rescue experiments showed that PDK1 inhibitors reversed the enhancement of cell proliferation, migration and glucose metabolism by miR-130a-3p inhibitor in Hep3B cells. In terms of mechanism, overexpression of miR-130a-3p targeted and inhibited the expression of PDK1, after which pyruvate dehydrogenase (PDH) is activated, thus glycolysis is inhibited, the production of lactic acid and ATP is reduced, and the ability to proliferate and migrate in HCC cells is weakened. In conclusion, our study highlights efforts to target PDK1 and miR-130a-3p as potential therapeutic strategies for the treatment of HCC.

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