EHMT2 Inhibition Induces Cell Death in Human Non-Small Cell Lung Cancer by Altering the Cholesterol Biosynthesis Pathway

Abstract

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.

Cholesterol promotes EGFR-TKIs resistance in NSCLC by inducing EGFR/Src/Erk/SP1 signaling-mediated ERRα re-expression

“…Cholesterol as an important component of lipids contribute to rapid cancer cell growth, metastasis and drug resistance [ 41 ]. Recently, the alteration of cholesterol homeostasis was reported in NSCLC as a result of dysregulation in cholesterol synthesis, uptake or trafficking process [ 17 , 42 ]. In the present study, we found upregulated cholesterol level in both gefitinib-resistant PC-9/GR, H1975 cells and osimertinib-resistant PC-9/OR cells.…”

Neurotrophins as Key Regulators of Cell Metabolism: Implications for Cholesterol Homeostasis

“…The euchromatic histone-lysine N-methyltransferase 2 (EHMT2) acts as a cholesterol biosynthesis suppressor. EHMT2 inhibition by BIX01294 induces the expression of srebf2 (encoding for SREBP2) through the reduction of H3K9me1 and H3K9me2 at the promoter [ 151 ]. Other reports also revealed that cholesterol biosynthesis may be strongly affected by the activity of bromo- and extra-terminal domain (BET) proteins, namely BRD2, BRD3, BRD4 and BRDT.…”

BIX01294 inhibits EGFR signaling in EGFR-mutant lung adenocarcinoma cells through a BCKDHA-mediated reduction in the EGFR level

“…BIX01294 has been reported to exert antitumor effects against a variety of cancers [15][16][17][18][19] , including lung cancer 20,21,30 , but the precise mechanisms of these effects, particularly in NSCLCs, remain unclear. In our present study, we proposed a unique mechanism by which BIX01294 has antitumor effects, particularly on EGFR-mutant NSCLCs, by blocking BCAA metabolism-mediated maintenance of the EGFR level through inhibition of the activity of Jumonji histone demethylases, particularly KDM3A.…”

“…Of note, BIX was found to suppress cell proliferation and trigger apoptotic cell death in lung cancer by downregulating Bcl-2 expression 20 . Furthermore, BIX was shown in another report to reduce the viability of NSCLC cells through induction of autophagy 21 . However, the precise mechanisms underlying this antitumor activity of BIX, particularly in relation to EGFR signaling, remain largely unknown.…”