Reprogramming metabolism by histone methyltransferase NSD2 drives endocrine resistance via coordinated activation of pentose phosphate pathway enzymes

Abstract

A B S T R A C TMetabolic reprogramming such as the aerobic glycolysis or Warburg effect is well recognized as a common feature of tumorigenesis. However, molecular mechanisms underlying metabolic alterations for tumor therapeutic resistance are poorly understood. Through gene expression profiling analysis we found that histone H3K36 methyltransferase NSD2/MMSET/WHSC1 expression was highly elevated in tamoxifenresistant breast cancer cell lines and clinical tumors. IHC analysis indicated that NSD2 protein overexpression was associated with the disease recurrence and poor survival. Ectopic expression of NSD2 wild type, but not the methylase-defective mutant, drove endocrine resistance in multiple cell models and xenograft tumors. Mechanistically, NSD2 was recruited to and methylated H3K36me2 at the promoters of key glucose metabolic enzyme genes. Its overexpression coordinately up-regulated hexokinase 2 (HK2) and glucose-6-phosphate dehydrogenase (G6PD), two key enzymes of glycolysis and the pentose phosphate pathway (PPP), as well as TP53-induced glycolysis regulatory phosphatase TIGAR. Consequently, NSD2-driven tamoxifen-resistant cells and tumors displayed heightened PPP activity, elevated NADPH production, and reduced ROS level, without significantly altered glycolysis. These results illustrate a coordinated, epigenetic activation of key glucose metabolic enzymes in therapeutic resistance and nominate methyltransferase NSD2 as a potential therapeutic target for endocrine resistant breast cancer.© 2016 Elsevier Ireland Ltd. All rights reserved. IntroductionTumor growth involves reprogrammed glucose metabolism, featured in aerobic glycolysis, to meet the high demand of glycolytic intermediates for biosynthesis of macromolecules. The pentose phosphate pathway (PPP) is a major cellular source of NADPH, in addition to its supply of precursors for nucleotide biosynthesis. Deregulated PPP has been suggested to promote cancer progression and therapy resistance [1]. The activities of PPP can be decreased by p53, as well as being hyperactivated by oncogenic signaling [2][3][4][5]. Functioning as a fructose-2,6-bisphosphatase (F2,6bPase), TIGAR (TP53-induced glycolysis and apoptosis regulator) can enhance glucose carbon flux to the PPP by dampening glycolysis and is required for the development of intestinal adenomas [6][7][8][9]. As a glycolysis modulator, TIGAR was shown to localize in cytoplasm and associate with mitochondria in complex with the hexokinase HK2 in response to hypoxia [7]. HK2, one of the hexokinases that catalyze the first and rate-limiting step of glucose metabolism, is highly expressed in most tumor cells. HK2 plays a pivotal role in diversion of glucose into pathways such as the PPP for enhanced anabolic metabolism required for tumor growth [10,11]. Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the PPP and plays a key role in production of NADPH, the major cellular source of reducing power. However, the mechanism of how the different metabolic genes are coordinately regulat...

Role of Brf1 interaction with ERα, and significance of its overexpression, in human breast cancer

“…Resistance to endocrine therapies is a major issue in recurrent ER+ HBC patients (De Marchi et al ., 2016). Several mechanisms have been connected to endocrine resistance, such as mutation in the ligand‐binding domain of the ER (Toy et al ., 2013), enhanced growth factor signaling, altered DNA methylation of specific genes (Graff et al ., 1995; Widschwendter and Jones, 2002), or the dysregulation of metabolic pathways (Wang et al ., 2016). In our study, we discovered a novel mechanism demonstrating that Tam decreases Brf1 expression and Pol III gene transcription (Fig.…”

NSD2 is downregulated in T2DM and promotes β cell proliferation and insulin secretion through the transcriptionally regulation of PDX1

“…Previous studies have shown that NSD2 is up-regulated in multiple types of human cancers, including small-cell lung cancers, stomach cancer, neuroblastoma, colon cancer, hepatocellular carcinoma, ovarian carcinoma and prostate cancer (16)(17)(18)(19)(20)(21)(22). Furthermore, NSD2 has been demonstrated to support the proliferation and/or survival of many cancer cell lines, such as prostate cancer (22)(23)(24), myeloma cell lines with t (4;14) translocations (25)(26)(27)(28) and leukemia cell lines carrying the E1099K mutation (29), Wang et al (30) has found that NSD2 regulates glucose metabolism; however, whether NSD2 plays roles in diabetes has not been explored.…”

Dysregulation of histone methyltransferases in breast cancer – Opportunities for new targeted therapies?

“…While there is limited evidence of NSD1 dysregulation in breast cancer (Vougiouklakis et al., 2015), NSD2/MMSET overexpression is associated with tumor aggressiveness (Kassambara et al., 2009). Moreover, NSD2 may play a role in drug resistance, since tamoxifen‐resistant breast cancer cell lines have highly elevated NSD2, and only wild type NSD2, but not its methylase‐defective mutant conferred resistance to tamoxifen (Wang et al., 2016). Consistent with this, NSD2 overexpression is highly correlated with poor survival in tamoxifen‐treated patients (Wang et al., 2016).…”

“…Moreover, NSD2 may play a role in drug resistance, since tamoxifen‐resistant breast cancer cell lines have highly elevated NSD2, and only wild type NSD2, but not its methylase‐defective mutant conferred resistance to tamoxifen (Wang et al., 2016). Consistent with this, NSD2 overexpression is highly correlated with poor survival in tamoxifen‐treated patients (Wang et al., 2016). Notably, NSD2/MMSET and the H3K27 methyltransferase EZH2 (discussed below) are co‐expressed at high levels in cancers including breast and prostate in which EZH2's oncogenic activity was reported to require NSD2/MMSET (Asangani et al., 2013).…”