Basic Nuclear Processes Affected by Histone Acetyltransferases and Histone Deacetylase Inhibitors

Abstract

Aim: The optimal balance between histone acetylation and deacetylation is important for proper gene function. Therefore, we addressed how inhibitors of histone-modifying enzymes can modulate nuclear events, including replication, transcription, splicing and DNA repair. Materials & methods: Changes in cell signaling pathways upon treatment with histone acetyltransferases and/or histone deacetylase inhibitors were studied by cDNA microarrays and western blots. Results: We analyzed the effects of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) and the histone acetylase inhibitor MG149. SAHA altered the expression of factors involved in DNA replication complexes, basal transcription and the spliceosome pathway. DNA repair-related genes, including Rad51, Rad54 and BRCA2, were significantly downregulated by SAHA. However, MG149 had no effect on the investigated nuclear processes, with the exception of the spliceosome network and Sestrins, involved in DNA repair. Conclusion: Based on our results, we propose that the studied epigenetic drugs have the distinct potential to affect specific cell signaling pathways depending on their respective molecular targets.

KEYWORDS::

• cDNA microarray
• DNA repair
• epi-drug
• HAT
• HDAC
• histone acetylation
• nuclear process
• p53
• replication
• splicing
• transcription
• tumor cell

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/3dp-2022-0019

Financial & competing interests disclosure

This work was supported by the EU Marie Curie project PIRSES-GA-2010-269156-LCS, the national COST-CZ project LD11020, COST EU project TD0905 and the Grant Agency of the Czech Republic (projects P302/10/1022, P302/12/G157 and 13-07822S). The postdoctoral fellowship of L Stixová was covered by Education for Competitiveness Operational Programme (ECOP) project CZ.1.07/2.3.00/30.0030. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

English correction was provided by BioScience Writers (TX, USA) and funded by the Grant Agency of the Czech Republic (project number 13-07822S).

Ethical conduct of research

Human embryonic stem cells were purchased and maintained according to the Czech Republic national law 227/2006, and Ethics Committee agreement No. 616/2012-31. K562 and MOLP8 cells are commercially available from Leibniz Institute DSMZ or K562 cells from the European Collection of Cell Cultures, Salisbury, UK.

Additional information

Funding

This work was supported by the EU Marie Curie project PIRSES-GA-2010-269156-LCS, the national COST-CZ project LD11020, COST EU project TD0905 and the Grant Agency of the Czech Republic (projects P302/10/1022, P302/12/G157 and 13-07822S). The postdoctoral fellowship of L Stixová was covered by Education for Competitiveness Operational Programme (ECOP) project CZ.1.07/2.3.00/30.0030. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. English correction was provided by BioScience Writers (TX, USA) and funded by the Grant Agency of the Czech Republic (project number 13-07822S).