Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer. Besides genetic and environmental factors, epigenetic alterations contribute to the tumorigenesis of NSCLC. Epigenetic changes are considered key drivers of cancer initiation and progression, and altered expression and activity of epigenetic modifiers reshape the epigenetic landscape in cancer cells. Euchromatic histone-lysine N-methyltransferase 2 (EHMT2) is a histone methyltransferase and catalyzes monoand di-methylation at histone H3 lysine 9 (H3K9me1 and H3K9me2, respectively), leading to gene silencing. EHMT2 overexpression has been reported in various types of cancer, including ovarian cancer and neuroblastoma, in relation to cell proliferation and metastasis. However, its role in NSCLC is not fully understood. In this study, we showed that EHMT2 gene expression was higher in NSCLC than normal lung tissue based on publicly available data. Inhibition of EHMT2 by BIX01294 (BIX) reduced cell viability of NSCLC cell lines via induction of autophagy. Through RNA sequencing analysis, we found that EHMT2 inhibition significantly affected the cholesterol biosynthesis pathway. BIX treatment directly induced the expression of SREBF2, which is a master regulator of cholesterol biosynthesis, by lowering H3K9me1 and H3K9me2 at the promoter. Treatment of a cholesterol biosynthesis inhibitor, 25-hydroxycholesterol (25-HC), partially recovered BIX-induced cell death by attenuating autophagy. Our data demonstrated that EHMT2 inhibition effectively induced cell death in NSCLC cells through altering cholesterol metabolism-dependent autophagy.

Cancer metabolism is considered as one of major cancer hallmarks. It is important to understand cancer-specific metabolic changes and its impact on cancer biology to identify therapeutic potentials. Among cancer-specific metabolic changes, a role of serine metabolism has been discovered in various cancer types. Upregulation of serine synthesis pathway (SSP) supports cell proliferation and metastasis. The change of serine metabolism is, in part, mediated by epigenetic modifiers, such as Euchromatic histone-lysine N-methyltransferase 2 and Lysine Demethylase 4C. On the other hand, SSP also influences epigenetic landscape such as methylation status of nucleic acids and histone proteins via affecting S-adenosyl methionine production. In the review, we highlight recent evidences on interactions between SSP and epigenetic regulation in cancer. It may provide an insight on roles and regulation of SSP in cancer metabolism and the potential of serine metabolism for cancer therapy.

Although family with sequence similarity 188 member B (FAM188B) is known to be a member of a novel putative deubiquitinase family, its biological role has not been fully elucidated. Here, we demonstrate the oncogenic function of FAM188B via regulation of forkhead box M1 (FOXM1), another oncogenic transcription factor, in lung cancer cells. FAM188B knockdown induced the inhibition of cell growth along with the downregulation of mRNA and protein levels of FOXM1. FAM188B knockdown also resulted in downregulation of Survivin and cell cycle-related proteins, which are direct targets of FOXM1. Interestingly, FOXM1 co-immunoprecipitated with FAM188B, and the levels of FOXM1 ubiquitination increased with FAM188B knockdown but decreased with FAM188B overexpression. In addition, in vivo xenograft of FAM188B siRNA (siFAM188B) RNA-treated cells resulted in the retardation of tumor growth compared with that in the control. Furthermore, protein levels of FAM188B and FOXM1 were elevated in the human lung cancer tissues, and FAM188B expression was negatively correlated with the overall survival of lung cancer patients. These results indicate that FAM188B exerts its oncogenic effects by regulating FOXM1 deubiquitination and thus its stability. Therefore, FAM188B might be a potential therapeutic target to control lung cancer progression.

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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.