br Introduction Metabolic cues are crucial inputs in dictati

Introduction Metabolic cues are crucial inputs in dictating acute responses through governing cellular signaling pathways as well as in shaping up long-term transcriptional and epigenetic profiles to control chronic cellular responses (Lu and Thompson, 2012). It has been well documented that metabolites, including acetyl-CoA and α-ketoglutarate, actively participate in histone acetylation and demethylation, respectively (Cai et al., 2011; Klose and Zhang, 2007). However, given the nature of metabolites, that they are small molecules and essential to many different cellular processes, metabolites are not considered favorable therapeutic targets (Vander Heiden, 2011). Therefore, defining crucial metabolite sensor proteins that are capable of monitoring and coupling metabolic messages directly with BAY 87-2243 changes to govern cellular responses would be of great translational value (Vander Heiden, 2011). To this end, mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) have been characterized as the two most important sensors for energy surplus and deprivation state, respectively. Importantly, mTOR is activated by the energy surplus conditions (Zoncu et al., 2011), whereas AMPK is largely activated by elevated cellular ADP or AMP level that is coupled to energy shortage state (Hardie et al., 2012). During the past decade, even though the functions of AMPK in metabolism, protein synthesis, and autophagy have been well characterized (Herzig and Shaw, 2017), its mechanistic role in global epigenetic alterations that play critical roles in defining cellular chronic reactions to energy state remains less explored. In addition to its canonical function to govern energy homeostasis, accumulating evidence suggests that AMPK also plays crucial roles in tumorigenesis partly through modulating the expression of genes critical for tumor cell growth and survival (Cheng et al., 2016). Hence, we were interested in revealing the potential role and molecular mechanism(s) of AMPK in regulating epigenetic marks on chromatin to control the fate of cancer cells. Polycomb repressive complex 2 (PRC2) plays a central role in controlling important cellular processes such as maintaining stem cell pluripotency and promoting cell proliferation (Margueron and Reinberg, 2011). As the primary catalytic subunit of the PRC2 complex, EZH2 methylates histone H3 lysine 27 (H3K27) primarily at promoters of target genes (Melnick, 2012), and trimethylated H3K27 (H3K27me3) in turn recruits PRC1 to the target gene promoters, where PRC1 catalyzes mono-ubiquitination of histone H2A at Lys 119 (Sauvageau and Sauvageau, 2010). These epigenetic modifications in the promoter region act in concert to facilitate epigenetic silencing of target genes (Margueron and Reinberg, 2011). The core PRC2 complex contains three subunits, the catalytic subunit EZH2 or EZH1, and the scaffolding components SUZ12 and EED. In addition to these core subunits, RbAp46/48 (also known as RBBP7/4), zinc-finger protein AEBP2, tudor domain-containing protein PCL isoforms, and Jumonji family protein JARID2 have been shown in complex with the core PRC2 complex to either enhance the enzymatic activity of PRC2 or tether PRC2 to the targeted gene loci (Margueron and Reinberg, 2011). PRC2 is a stable protein complex; depleting any of its core components resulted in a decreased expression of other subunits (Cao et al., 2002; Cao and Zhang, 2004). This finding is supported by the observation that Ezh2−/−, Eed−/−, and Suz12−/− embryonic stem cells (ESCs) all displayed deficiency in maintaining pluripotency (Margueron and Reinberg, 2011), suggesting that the integrity of the PRC2 core complex is essential to its enzymatic activity. EZH2 mutations or amplifications have been found in a broad spectrum of human cancers including B cell lymphoma, ovarian cancer, breast cancer, melanoma, bladder cancer, gastric cancer, and other cancers (Kim and Roberts, 2016). Given the evidence of EZH2 as a cancer driver, numerous efforts have been made that led to the development of EZH2 inhibitory compounds including EPZ-6438 (Knutson et al., 2013) and GSK126 (McCabe et al., 2012), both of which are currently used in clinical trials primarily against EZH2-mutated B cell lymphoma and advanced solid tumors (Kim and Roberts, 2016). However, mixed responses of anti-EZH2 single-agent therapies have been reported in both clinical and pre-clinical studies, particularly in the settings of solid tumors, advocating novel combination therapies for EZH2 hyperactive solid tumor patients (Kim and Roberts, 2016).