The histone deacetylases HDAC1 and HDAC2 are required for the growth and survival of renal carcinoma cells

The histone deacetylases HDAC1 and HDAC2 are required for the growth and survival of renal... Novel therapies are required for the treatment of metastatic renal cell carcinoma (RCC), which is associated with inoperable disease and patient death. Histone deacetylases (HDACs) are epigenetic modifiers and potential drug targets. Additional information on molecular pathways that are altered by histone deacetylase inhibitors (HDACi) in RCC cells is warranted. It should equally be delineated further which individual members of the 18 mammalian HDACs determine the survival and tumor-associated gene expression programs of such cells. Most importantly, an ongoing dispute whether HDACi promote or suppress metastasis-associated epithelial-to-mesenchymal transition (EMT) has to be resolved before HDACi are considered further as clinically relevant drugs. Here we show how HDACi affect murine and primary human RCC cells. We find that these agents induce morphological alterations resembling the metastasis-associated EMT. However, individual and proteomics-based analyses of epithelial and mesenchymal marker proteins and of EMT-associated transcription factors (EMT-TFs) reveal that HDACi do not trigger EMT. Pathway deconvolution analysis identifies reduced proliferation and apoptosis induction as key effects of HDACi. Furthermore, these drugs lead to a reduction of the cell adhesion molecule E-cadherin and of the platelet-derived growth factor receptor-β (PDGFRβ), which is a key driver of RCC metastasis formation. Accordingly, HDACi reduce the pulmonary spread of syngeneic transplanted renal carcinoma cells in mice. Specific genetic elimination of the histone deacetylases HDAC1/HDAC2 reflects the effects of pharmacological HDAC inhibition regarding growth suppression, apoptosis, and the downregulation of E-cadherin and PDGFRβ. Thus, these epigenetic modifiers are non-redundant gatekeepers of cell fate and precise pharmacological targets. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Toxicology Springer Journals

The histone deacetylases HDAC1 and HDAC2 are required for the growth and survival of renal carcinoma cells

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Publisher
Springer Journals
Copyright
Copyright © 2018 by Springer-Verlag GmbH Germany, part of Springer Nature
Subject
Biomedicine; Pharmacology/Toxicology; Occupational Medicine/Industrial Medicine; Environmental Health; Biomedicine, general
ISSN
0340-5761
eISSN
1432-0738
D.O.I.
10.1007/s00204-018-2229-5
Publisher site
See Article on Publisher Site

Abstract

Novel therapies are required for the treatment of metastatic renal cell carcinoma (RCC), which is associated with inoperable disease and patient death. Histone deacetylases (HDACs) are epigenetic modifiers and potential drug targets. Additional information on molecular pathways that are altered by histone deacetylase inhibitors (HDACi) in RCC cells is warranted. It should equally be delineated further which individual members of the 18 mammalian HDACs determine the survival and tumor-associated gene expression programs of such cells. Most importantly, an ongoing dispute whether HDACi promote or suppress metastasis-associated epithelial-to-mesenchymal transition (EMT) has to be resolved before HDACi are considered further as clinically relevant drugs. Here we show how HDACi affect murine and primary human RCC cells. We find that these agents induce morphological alterations resembling the metastasis-associated EMT. However, individual and proteomics-based analyses of epithelial and mesenchymal marker proteins and of EMT-associated transcription factors (EMT-TFs) reveal that HDACi do not trigger EMT. Pathway deconvolution analysis identifies reduced proliferation and apoptosis induction as key effects of HDACi. Furthermore, these drugs lead to a reduction of the cell adhesion molecule E-cadherin and of the platelet-derived growth factor receptor-β (PDGFRβ), which is a key driver of RCC metastasis formation. Accordingly, HDACi reduce the pulmonary spread of syngeneic transplanted renal carcinoma cells in mice. Specific genetic elimination of the histone deacetylases HDAC1/HDAC2 reflects the effects of pharmacological HDAC inhibition regarding growth suppression, apoptosis, and the downregulation of E-cadherin and PDGFRβ. Thus, these epigenetic modifiers are non-redundant gatekeepers of cell fate and precise pharmacological targets.

Journal

Archives of ToxicologySpringer Journals

Published: May 29, 2018

References

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