EZH affects cancer by regulating the expression of target

EZH2 affects cancer by regulating the expression of target genes [22]. EZH2, together with SUZ12 and EED, forms the polycomb repressive complex 2 (PRC2), which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) [23,24]. PRC2 may recruit other polycomb complexes, DNA methyltransferases, and histone deacetylases, resulting in additional transcriptional repressive marks and chromatin compaction at key developmental loci [25,26]. We examined the trimethylationstatus of histone H3 lysine 27 (H3K27me3). Enforced expression of EZH2 caused increased accumulation of H3K27me3 in EJ and T24 Eplerenone sale exposed to curcumol, which indicates that EZH2modulates the mitochondrial apoptosis pathway by promoting trimethylation of histone H3 lysine 27.
Acknowledgments This project is supported by the Innovation project of Guangxi Graduate Education (YCSZ2015219), the Natural science foundation of Guangxi Province (NO. 2016GXNSFAA380305) and Guilin Scientific Research and Technology Development project (NO. 2016012706-15).
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 chromatin 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.