Direct monitoring of breast and endometrial cancer cell epigenetic response to DNA methyltransferase and histone deacetylase inhibitors

• Published in: Biosensors & bioelectronics 2019-09, Vol.141, p.111386-111386, Article 111386
• Main Authors: Teixeira, S.R., Abreu, C.M., Parkes, L., Davies, J., Yao, S., Sawhney, M.A., Margarit, L., Gonzalez, D., Pinto, I. Mendes, Francis, L.W., Conlan, R.S.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Biosensing Techniques - methods; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Cancer cell lines; Cell Line, Tumor; Dielectric Spectroscopy - methods; DNA methylation; DNA Methylation - drug effects; DNA Modification Methylases - antagonists & inhibitors; DNA Modification Methylases - metabolism; Drug Screening Assays, Antitumor - methods; EIS; Endometrial Neoplasms - drug therapy; Endometrial Neoplasms - genetics; Epigenesis, Genetic - drug effects; Epigenetics; Female; Histone acetylation; Histone Deacetylase Inhibitors - pharmacology; Humans
• ISSN: 0956-5663; 1873-4235
• DOI: 10.1016/j.bios.2019.111386

DNA methylation and histone deacetylation are key epigenetic processes involved in normal cellular function and tumorigenesis. Therapeutic strategies based on DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors are currently in use and under development for the treatment of cancers. Genome-wide DNA methylation profiling has been proposed for use in disease diagnosis, and histone modification profiling for disease stratification will follow suit. However, whether epigenome sequencing technologies will be feasible for rapid clinic diagnosis and patient treatment monitoring remains to be seen, and alternative detection technologies will almost certainly be needed. Here we used electrochemical impedance spectroscopy (EIS) employing a graphene-based screen-printed electrode system to directly measure global DNA methylation and histone H3 acetylation to compare non-cancer and breast cancer cell lines. We demonstrated that whilst global methylation was not useful as a differential marker in the cellular systems tested, histone H3 acetylation was effective at higher chromatin levels. Using breast and endometrial cancer cell models, EIS was then used to monitor cellular responses to the DNMT and HDAC inhibitors 5-Aza-2′-deoxycytidine and suberoylanilide hydroxamic acid in vitro, and proved very effective at detecting global cellular responses to either treatment, indicating that this approach could be useful in following treatment response to epigenetic drugs. Moreover, this work reports the first combined analysis of two epigenetic markers using a unified graphene-based biosensor platform, demonstrating the potential for multiplex analysis of both methylation and acetylation on the same sample. •Label and amplification-free graphene electrochemical immunosensor for the direct global assessment of methylated DNA and histone H3 acetylated chromatin levels.•System application demonstrated global alterations in DNA methylation or histone H3 acetylation in response to treatment with decitabine and vorinostat respectively.•Results were corroborated using established techniques including ChIP and MeDIP.•Point-of-care monitoring of patient responses to epigenetic therapeutics, and multiplex epigenetic marker detection on a unified platform.