Epigenetic Effects of Chromatin Remodeling Agents on Organotypic Cultures

Abstract

Background: Tumor epigenetic defects are of increasing relevance to clinical practice, because they are ‘druggable’ targets for cancer therapy using chromatin-remodeling agents (CRAs). New evidences highlight the importance of the microenvironment on the epigenome regulation and the need to use culture models able to preserve tissue morphology, to better understand the action of CRAs. Methods & methods: We studied the epigenetic response induced by culturing and CRAs in a preclinical model, preserving ex vivo the original tissue microenvironment and morphology, assessing different epigenetic signatures. Our overall findings suggest that culturing and CRAs cause heterogeneous effects on the genes methylation; CRAs affect the global DNA methylation and can trigger an active DNA demethylation; the culture induces alterations in the histone deacetylase expression. Conclusion: Despite the limited number of cases, these findings can be considered a proof of concept of the possibility to test CRAs epigenetic effects on ex vivo tissues maintained in their native tissue architecture.

Keywords::

• chromatin remodeling agents
• DNA hydroxymethylation
• DNA methylation
• epigenetics
• HDAC
• organotypic culture

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: http://www.tandfonline.com/doi/full/10.2217/epi.15.111

Author contributions

SM Sirchia conceived, designed, conducted the study and wrote the manuscript. M Miozzo, S Bosari and S Tabano contributed to study design and manuscript preparation. A Faversani, D Rovina, Maria V Russo, L Paganini, F Savi and C Augello performed laboratory experiments, data interpretation and contributed to figure preparation and manuscript reviewing. F Savi and A Del Gobbo performed pathological and immunohistochemical evaluations. L Rosso provided samples and contributed to data interpretation. All authors read and approved the manuscript.

Financial & competing interests disclosure

This work was supported by grant from the Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico: “5X1000” (Grant Number 519-01) to M Miozzo. 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.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This work was supported by grant from the Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico: “5X1000” (Grant Number 519-01) to M Miozzo. 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. No writing assistance was utilized in the production of this manuscript.