Abstract 4096: Correction of metabolically sensitive histone epigenetic marks mediates the drug sensitivity of MDA-MB-231 human breast cancer cells

Abstract

Abstract Evidence is accumulating that epigenetic alterations are major determinants of breast cancer progression. In a previous study we demonstrated that specific patterns of histone modifications correlated with changes in histone modifying enzymes in human breast cancer cells. More importantly, these changes were metabolically sensitive and differed between cells with epithelial and mesenchymal phenotypes, suggesting that they can be used as diagnostic and prognostic epigenetic biomarkers for breast cancer progression. We have now investigated whether or not metabolic targeting of the epigenome may be used for the treatment of breast cancer. Exposure of breast cancer cells to Compound 968, an allosteric inhibitor of glutaminase (GLS1), which we demonstrated previously to increase global histone H4 lysine 16 acetylation levels in mesenchymal MDA-MB-231 cells versus epithelial T-47D cells, resulted in a marked inhibition of cancer cell growth, with the effects being more prominent in mesenchymal MDA-MB-231 cells than epithelial T-47D cells. The growth inhibitory effect of Compound 968 in MDA-MB-231 breast cancer cells was accompanied by modest changes in H4 lysine 16 acetylation and a decreased level of histone H4 lysine 20 trimethylation at the promoter of tumor suppressor genes (e.g., CDH1), with a concordant rise in expression of the transcriptionally silenced CDH1 gene. Although, Compound 968 did not restore fully CDH1 expression in MDA-MB-231 to the level observed in epithelial T-47D cells, the observed increase in expression may lead to formation of a less aggressive cancer phenotype in MDA-MB-231 cancer cells and increase their sensitivity to chemotherapeutic agents. Indeed, a combined treatment of Compound 968 and the conventional chemotherapeutic drug cisplatin substantially increased the sensitivity of MDA-MB-231 cells to cisplatin. These results indicate that correcting of cancer-related metabolic disturbances may be an effective method for the targeted treatment of the cellular epigenome in aggressive breast cancer and may be useful for improving of the clinical management of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4096. doi:1538-7445.AM2012-4096