Targeting developmental regulators of zebrafish exocrine pancreas as a therapeutic approach in human pancreatic cancer

Histone deacetylases (HDACs) and RNA polymerase III (POLR3) play vital roles in fundamental cellular processes, and deregulation of these enzymes has been implicated in malignant transformation. Hdacs and Polr3 are required for exocrine pancreatic epithelial proliferation during morphogenesis in zeb...

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Main Authors:	Yee, Nelson S., Zhou, Weiqiang, Chun, Stephen G., Liang, I-Chau, Yee, Rosemary K.
Format:	Online
Language:	English
Published:	The Company of Biologists 2012
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509454/

id	pubmed-3509454
recordtype	oai_dc
spelling	pubmed-35094542012-12-04 Targeting developmental regulators of zebrafish exocrine pancreas as a therapeutic approach in human pancreatic cancer Yee, Nelson S. Zhou, Weiqiang Chun, Stephen G. Liang, I-Chau Yee, Rosemary K. Research Article Histone deacetylases (HDACs) and RNA polymerase III (POLR3) play vital roles in fundamental cellular processes, and deregulation of these enzymes has been implicated in malignant transformation. Hdacs and Polr3 are required for exocrine pancreatic epithelial proliferation during morphogenesis in zebrafish. We aim to test the hypothesis that Hdacs and Polr3 cooperatively control exocrine pancreatic growth, and combined inhibition of HDACs and POLR3 produces enhanced growth suppression in pancreatic cancer. In zebrafish larvae, combination of a Hdac inhibitor (Trichostatin A) and an inhibitor of Polr3 (ML-60218) synergistically prohibited the expansion of exocrine pancreas. In human pancreatic adenocarcinoma cells, combination of the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) and ML-60218 produced augmented suppression of colony formation and proliferation, and induction of cell cycle arrest and apoptotic cell death. The enhanced cytotoxicity was associated with supra-additive upregulation of the pro-apoptotic regulator BAX and the cyclin-dependent kinase inhibitor p21CDKN1A. tRNAs have been shown to have pro-proliferative and anti-apoptotic roles, and SAHA-stimulated expression of tRNAs was reversed by ML-60218. These findings demonstrate that chemically targeting developmental regulators of exocrine pancreas can be translated into an approach with potential impact on therapeutic response in pancreatic cancer, and suggest that counteracting the pro-malignant side effect of HDAC inhibitors can enhance their anti-tumor activity. The Company of Biologists 2012-02-10 /pmc/articles/PMC3509454/ /pubmed/23213420 http://dx.doi.org/10.1242/bio.2012539 Text en © 2012. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by-nc-sa/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0/).
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Yee, Nelson S. Zhou, Weiqiang Chun, Stephen G. Liang, I-Chau Yee, Rosemary K.
spellingShingle	Yee, Nelson S. Zhou, Weiqiang Chun, Stephen G. Liang, I-Chau Yee, Rosemary K. Targeting developmental regulators of zebrafish exocrine pancreas as a therapeutic approach in human pancreatic cancer
author_facet	Yee, Nelson S. Zhou, Weiqiang Chun, Stephen G. Liang, I-Chau Yee, Rosemary K.
author_sort	Yee, Nelson S.
title	Targeting developmental regulators of zebrafish exocrine pancreas as a therapeutic approach in human pancreatic cancer
title_short	Targeting developmental regulators of zebrafish exocrine pancreas as a therapeutic approach in human pancreatic cancer
title_full	Targeting developmental regulators of zebrafish exocrine pancreas as a therapeutic approach in human pancreatic cancer
title_fullStr	Targeting developmental regulators of zebrafish exocrine pancreas as a therapeutic approach in human pancreatic cancer
title_full_unstemmed	Targeting developmental regulators of zebrafish exocrine pancreas as a therapeutic approach in human pancreatic cancer
title_sort	targeting developmental regulators of zebrafish exocrine pancreas as a therapeutic approach in human pancreatic cancer
description	Histone deacetylases (HDACs) and RNA polymerase III (POLR3) play vital roles in fundamental cellular processes, and deregulation of these enzymes has been implicated in malignant transformation. Hdacs and Polr3 are required for exocrine pancreatic epithelial proliferation during morphogenesis in zebrafish. We aim to test the hypothesis that Hdacs and Polr3 cooperatively control exocrine pancreatic growth, and combined inhibition of HDACs and POLR3 produces enhanced growth suppression in pancreatic cancer. In zebrafish larvae, combination of a Hdac inhibitor (Trichostatin A) and an inhibitor of Polr3 (ML-60218) synergistically prohibited the expansion of exocrine pancreas. In human pancreatic adenocarcinoma cells, combination of the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) and ML-60218 produced augmented suppression of colony formation and proliferation, and induction of cell cycle arrest and apoptotic cell death. The enhanced cytotoxicity was associated with supra-additive upregulation of the pro-apoptotic regulator BAX and the cyclin-dependent kinase inhibitor p21CDKN1A. tRNAs have been shown to have pro-proliferative and anti-apoptotic roles, and SAHA-stimulated expression of tRNAs was reversed by ML-60218. These findings demonstrate that chemically targeting developmental regulators of exocrine pancreas can be translated into an approach with potential impact on therapeutic response in pancreatic cancer, and suggest that counteracting the pro-malignant side effect of HDAC inhibitors can enhance their anti-tumor activity.
publisher	The Company of Biologists
publishDate	2012
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509454/
_version_	1611936376056446976

Targeting developmental regulators of zebrafish exocrine pancreas as a therapeutic approach in human pancreatic cancer

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