Abstract
PurposeWe set out to determine whether clinically tested epigenetic drugs against class I histone deacetylases (HDACs) affect hallmarks of the metastatic process.MethodsWe treated permanent and primary renal, lung, and breast cancer cells with the class I histone deacetylase inhibitors (HDACi) entinostat (MS-275) and valproic acid (VPA), the replicative stress inducer hydroxyurea (HU), the DNA-damaging agent cis-platinum (L-OHP), and the cytokine transforming growth factor-β (TGFβ). We used proteomics, quantitative PCR, immunoblot, single cell DNA damage assays, and flow cytometry to analyze cell fate after drug exposure.ResultsWe show that HDACi interfere with DNA repair protein expression and trigger DNA damage and apoptosis alone and in combination with established chemotherapeutics. Furthermore, HDACi disrupt the balance of cell adhesion protein expression and abrogate TGFβ-induced cellular plasticity of transformed cells.ConclusionHDACi suppress the epithelial–mesenchymal transition (EMT) and compromise the DNA integrity of cancer cells. These data encourage further testing of HDACi against tumor cells.
Highlights
The formation of metastases that originate from a primary cancer is commonly associated with increased drug resistance and patient death (Fidler and Kripke 2015)
We recently revealed that histone deacetylase inhibitors (HDACi) did not shift renal cell carcinoma (RCC) cells to a distinct epithelial or mesenchymal phenotype, but rather disrupted functional epithelial–mesenchymal transition (EMT)/MET protein expression signatures and triggered apoptosis of RCC cells (Kiweler et al 2018)
Due to the rising interest in the impact of histone deacetylases (HDACs) and HDACi on DNA replication and DNA integrity, we analyzed the expression levels of proteins that control replicative stress and DNA damage in a previously published proteome database for MS-275-treated Renca cells (Kiweler et al 2018). This analysis showed that HDAC inhibition by MS-275 decreased the expression of proteins that control homologous recombination (HR), DNA mismatch repair (MMR), nucleotide excision repair (NER), and base excision repair (BER) in Renca cells (Fig. 1a and Supplementary Fig. S1)
Summary
The formation of metastases that originate from a primary cancer is commonly associated with increased drug resistance and patient death (Fidler and Kripke 2015). Breast and pancreatic cancer cells represents predominantly an indicator of cellular resistance to DNA damage (Aiello et al 2017; Brabletz et al 2018; Fischer et al 2015; Ye et al 2017; Zheng et al 2015) Irrespective of this conceptual conflict, it is undoubted that novel drugs are necessary to combat clinical metastasis formation to enhance patient survival. We recently revealed that HDACi did not shift renal cell carcinoma (RCC) cells to a distinct epithelial or mesenchymal phenotype, but rather disrupted functional EMT/MET protein expression signatures and triggered apoptosis of RCC cells (Kiweler et al 2018). In light of the chemoresistance and the poor prognosis of metastatic RCC (Barbieri et al 2017; Chang et al 2019), these findings suggest that HDACi pose an interesting therapeutic option for this cancer type
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