HDAC11 Regulates Glycolysis through the LKB1/AMPK Signaling Pathway to Maintain Hepatocellular Carcinoma Stemness

Autor: Lei Bi, Fuqiong Zhou, Peng Meng, Bo Tang, Yidan Ren, Yunshan Wang, Yu-Cui Jiang, Weiping Chen, Qin Wang, Chuanxin Wang, Maoxiao Feng, Yuli Wang, Feiyan Chen, Qinlian Jiao, Lutao Du
Rok vydání: 2021
Předmět:
0301 basic medicine
Cancer Research
AMP-Activated Protein Kinases
medicine.disease_cause
Metastasis
Histones
Mice
0302 clinical medicine
AMP-Activated Protein Kinase Kinases
Conditional gene knockout
Promoter Regions
Genetic
Tumor Stem Cell Assay
Mice
Inbred BALB C
biology
Liver Neoplasms
Acetylation
Hep G2 Cells
Sorafenib
Prognosis
Histone
Oncology
030220 oncology & carcinogenesis
Disease Progression
Neoplastic Stem Cells
Glycolysis
Signal Transduction
medicine.drug
Carcinoma
Hepatocellular
Mice
Nude
Antineoplastic Agents
Protein Serine-Threonine Kinases
Histone Deacetylases
03 medical and health sciences
Cancer stem cell
Cell Line
Tumor
Spheroids
Cellular
Biomarkers
Tumor
medicine
Animals
Humans
Gene Silencing
neoplasms
HDAC11
Gene Expression Profiling
Cancer
medicine.disease
digestive system diseases
Disease Models
Animal
030104 developmental biology
Drug Resistance
Neoplasm
biology.protein
Cancer research
Energy Metabolism
Carcinogenesis
Zdroj: Cancer Research. 81:2015-2028
ISSN: 1538-7445
0008-5472
Popis: 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.
Databáze: OpenAIRE
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