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

Nicole Kiweler, Boris Brill, Matthias Wirth, Ines Breuksch, Teresa Laguna, Cornelia Dietrich, Susanne Strand, Günter Schneider, Bernd Groner, Falk Butter, Thorsten Heinzel, Walburgis Brenner, Oliver H. Krämer*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

40 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2227-2243
Number of pages17
JournalArchives of Toxicology
Volume92
Issue number7
DOIs
Publication statusPublished - 1 Jul 2018
Externally publishedYes

Keywords

  • EMT
  • HDAC1
  • HDAC2
  • HDACi
  • Proteomics
  • Renal cancer

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