Abstract PO-040: The role of mTOR in epigenetic regulation in cancer

Abstract

Changes in gene expression, including those caused by epigenetic dysregulation, represent a hallmark of cancer. The mechanistic/mammalian Target of Rapamycin (mTOR) is a serine/threonine kinase that coordinates nutrient availability to the regulation of cell growth and metabolism, which is frequently perturbed in cancer. mTOR exists in two structurally and functionally divergent complexes, mTOR complex 1 and 2 (mTORC1 and 2). mTORC1 regulates many metabolic pathways, including the serine-glycine-one carbon network (SGOC), a pathway modulating the production of S-adenosyl methionine (SAM) and α-ketoglutarate (α-KG). The latter two metabolites constitute essential co-substrates of histone methyltransferases and demethylases, respectively. However, how mTOR signaling controls epigenetic dynamics remains largely unknown. To address this important gap in knowledge, we treated two breast cancer cell lines (MCF7 and T47D) with allosteric (rapamycin) and active-site (INK128) mTOR inhibitors to study how mTOR may influence global histone methylation. We found that mTOR inhibitors significantly increased histone 3 lysine 9 tri-methylation (H3K9me3) and histone 3 lysine 27 tri-methylation (H3K27me3) but not histone 3 lysine 4 tri-methylation (H3K4me3) suggesting this effect was selective. Metabolomic tools were employed to decipher changes of epigenetic metabolites α-KG, SAM, S-Adenosyl homocysteine (SAH), methionine, and serine upon mTOR inhibition. These findings provide bases for my future work which will focus on establishing the role of alterations in mTOR signaling on epigenetic programs which drive tumorigenesis. A better understanding of this network may help identify new therapeutic targets to improve current cancer treatments. Citation Format: HaEun Kim, David Papadopoli, Ivan Topisirovic. The role of mTOR in epigenetic regulation in cancer [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-040.