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The HDAC6 inhibitor C1A modulates autophagy substrates in diverse cancer cells and induces cell death

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Title: The HDAC6 inhibitor C1A modulates autophagy substrates in diverse cancer cells and induces cell death
Authors: Kaliszczak, M
Hechanova, E
Alsadah, H
Li, M
Parzych, K
Auner, H
Aboagye, EO
Item Type: Journal Article
Abstract: BACKGROUND: Cytosolic Deacetylase HDAC6 is involved in the autophagy degradation pathway of malformed proteins, an important survival mechanism in cancer cells. We evaluated modulation of autophagy-related proteins and cell death by the HDAC6-selective inhibitor C1A. METHODS: Autophagy substrates (LC3 and p62 proteins) and endoplasmic reticulum (ER) stress phenotype were determined. Caspase 3/7 activation and cellular proliferation assays were used to assess consequences of autophagy modulation. RESULTS: C1A potently resolved autophagy substrates induced by 3-MA and chloroquine. The mechanism of autophagy inhibition by HDAC6 genetic knockout or C1A treatment was consistent with abrogation of autophagosome-lysosome fusion, and decrease of Myc protein. C1A alone or combined with the proteasome inhibitor, bortezomib, enhanced cell death in malignant cells demonstrating the complementary roles of the proteasome and autophagy pathways for clearing malformed proteins. Myc positive neuroblastoma, KRAS positive colorectal cancer and multiple myeloma cells showed marked cell growth inhibition in response to HDAC6 inhibitors. Finally, growth of neuroblastoma xenografts was arrested in vivo by single agent C1A, while combination with bortezomib slowed the growth of colorectal cancer xenografts. CONCLUSIONS: C1A resolves autophagy substrates in malignant cells and induces cell death, warranting its use for in vivo pre-clinical autophagy research.
Issue Date: 15-Oct-2018
Date of Acceptance: 25-Jul-2018
URI: http://hdl.handle.net/10044/1/62884
DOI: https://dx.doi.org/10.1038/s41416-018-0232-5
ISSN: 0007-0920
Publisher: Cancer Research UK
Start Page: 1278
End Page: 1287
Journal / Book Title: British Journal of Cancer
Volume: 119
Copyright Statement: © The Author(s) 2018. This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is not included in thearticle’s Creative Commons license and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directlyfrom the copyright holder. To view a copy of this license, visithttp://creativecommons.org/licenses/by/4.0/
Sponsor/Funder: Cancer Research UK
Funder's Grant Number: C2536/A16584
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
HISTONE DEACETYLASE 6
REGULATES AGGRESOME FORMATION
KINASE INHIBITOR
ANTITUMOR-ACTIVITY
N-MYC
COMBINATION
BORTEZOMIB
MECHANISMS
PROTEIN
DRUG
Oncology & Carcinogenesis
1112 Oncology and Carcinogenesis
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Department of Medicine
Faculty of Medicine



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