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Inhibition of histone deacetylase 6 destabilizes ERK phosphorylation and suppresses cancer proliferation via modulation of the tubulin acetylation-GRP78 interaction
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Document Title
Inhibition of histone deacetylase 6 destabilizes ERK phosphorylation and suppresses cancer proliferation via modulation of the tubulin acetylation-GRP78 interaction
Author
Wattanathamsan O. Chantaravisoot N. Wongkongkathep P. Kungsukool S. Chetprayoon P. Chanvorachote P. Vinayanuwattikun C. Pongrakhananon V.
Affiliations
Department of Pharmacology and Physiology Faculty of Pharmaceutical Sciences Chulalongkorn University Bangkok Thailand; Department of Biochemistry Faculty of Medicine Chulalongkorn University Bangkok Thailand; Center of Excellence in Systems Biology Faculty of Medicine Chulalongkorn University Bangkok Thailand; Department of Respiratory Medicine Central Chest Institute of Thailand Muang District Nonthaburi Thailand; Toxicology and Bio Evaluation Service Center National Science and Technology Development Agency Pathum Thani Thailand; Division of Medical Oncology Department of Medicine Faculty of Medicine Chulalongkorn University Bangkok Thailand; Preclinical Toxicity and Efficacy Assessment of Medicines and Chemicals Research Cluster Chulalongkorn University Bangkok Thailand
Type
Article
Source Title
Journal of Biomedical Science
ISSN
10217770
Year
2023
Volume
30
Issue
1
Open Access
All Open Access Gold Green
Publisher
BioMed Central Ltd
DOI
10.1186/s12929-023-00898-3
Abstract
Background: The leading cause of cancer-related mortality worldwide is lung cancer and its clinical outcome and prognosis are still unsatisfactory. The understanding of potential molecular targets is necessary for clinical implications in precision diagnostic and/or therapeutic purposes. Histone deacetylase 6 (HDAC6) a major deacetylase enzyme is a promising target for cancer therapy; however the molecular mechanism regulating cancer pathogenesis is largely unknown. Methods: The clinical relevance of HDAC6 expression levels and their correlation with the overall survival rate were analyzed based on the TCGA and GEO databases. HDAC6 expression in clinical samples obtained from lung cancer tissues and patient-derived primary lung cancer cells was evaluated using qRT朠CR and Western blot analysis. The potential regulatory mechanism of HDAC6 was identified by proteomic analysis and validated by immunoblotting immunofluorescence microtubule sedimentation and immunoprecipitation-mass spectrometry (IP-MS) assays using a specific inhibitor of HDAC6 trichostatin A (TSA) and RNA interference to HDAC6 (siHDAC6). Lung cancer cell growth was assessed by an in vitro 2-dimensional (2D) cell proliferation assay and 3D tumor spheroid formation using patient-derived lung cancer cells. Results: HDAC6 was upregulated in lung cancer specimens and significantly correlated with poor prognosis. Inhibition of HDAC6 by TSA and siHDAC6 caused downregulation of phosphorylated extracellular signal-regulated kinase (p-ERK) which was dependent on the tubulin acetylation status. Tubulin acetylation induced by TSA and siHDAC6 mediated the dissociation of p-ERK on microtubules causing p-ERK destabilization. The proteomic analysis demonstrated that the molecular chaperone glucose-regulated protein 78 (GRP78) was an important scaffolder required for p-ERK localization on microtubules and this phenomenon was significantly inhibited by either TSA siHDAC6 or siGRP78. In addition suppression of HDAC6 strongly attenuated an爄n vitro 2D lung cancer cell growth and an爄n vitro 3D patient derived-lung cancer spheroid growth. Conclusions: HDAC6 inhibition led to upregulate tubulin acetylation causing GRP78-p-ERK dissociation from microtubules. As a result p-ERK levels were decreased and lung cancer cell growth was subsequently suppressed. This study reveals the intriguing role and molecular mechanism of HDAC6 as a tumor promoter and its inhibition represents a promising approach for anticancer therapy. ? 2023 The Author(s).
Industrial Classification
Knowledge Taxonomy Level 1
Knowledge Taxonomy Level 2
Knowledge Taxonomy Level 3
License
CC BY
Rights
Authors
Publication Source
WOS