Abstract
Hepatocellular carcinoma (HCC) contains a subset of cancer stem cells (CSC) that cause tumor recurrence, metastasis, and chemical resistance. Histone deacetylase 11 (HDAC11) mediates diverse immune functions and metabolism, yet little is known about its role in HCC CSCs. In this study, we report that HDAC11 is highly expressed in HCC and is closely related to disease prognosis. Depletion of HDAC11 in a conditional knockout mouse model reduced hepatocellular tumorigenesis and prolonged survival. Loss of HDAC11 increased transcription of LKB1 by promoting histone acetylation in its promoter region, thereby activating the AMPK signaling pathway and inhibiting the glycolysis pathway, which in turn leads to the suppression of cancer stemness and HCC progression. Furthermore, HDAC11 overexpression reduced HCC sensitivity to sorafenib. Collectively, these data propose HDAC11 as a new target for combination therapy in patients with kinase-resistant HCC. SIGNIFICANCE: This study finds that HDAC11 suppresses LKB1 expression in HCC to promote cancer stemness, progression, and sorafenib resistance, suggesting the potential of targeting HDAC11 to treat HCC and overcome kinase inhibitor resistance.
©2021 American Association for Cancer Research.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinase Kinases
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AMP-Activated Protein Kinases / metabolism*
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Acetylation
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Animals
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Antineoplastic Agents / therapeutic use
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Biomarkers, Tumor / metabolism
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Carcinoma, Hepatocellular / drug therapy
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Carcinoma, Hepatocellular / metabolism*
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Carcinoma, Hepatocellular / mortality
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Carcinoma, Hepatocellular / pathology
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Cell Line, Tumor
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Disease Models, Animal
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Disease Progression
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Drug Resistance, Neoplasm
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Energy Metabolism
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Gene Expression Profiling
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Gene Silencing
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Glycolysis / physiology
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Hep G2 Cells
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Histone Deacetylases / deficiency
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism*
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Histones / metabolism
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Humans
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Liver Neoplasms / drug therapy
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Liver Neoplasms / metabolism*
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Liver Neoplasms / mortality
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Liver Neoplasms / pathology
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Prognosis
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Promoter Regions, Genetic
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Protein Serine-Threonine Kinases / metabolism*
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Signal Transduction
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Sorafenib / therapeutic use
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Spheroids, Cellular / metabolism
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Tumor Stem Cell Assay
Substances
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Antineoplastic Agents
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Biomarkers, Tumor
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Histones
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Sorafenib
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Protein Serine-Threonine Kinases
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STK11 protein, human
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AMP-Activated Protein Kinase Kinases
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AMP-Activated Protein Kinases
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HDAC11 protein, human
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Histone Deacetylases