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  • gamma-Glu-Cys We recently identified a G A dependent epigene


    We recently identified a G9A-dependent epigenetic mechanism for transcriptional activation of the serine pathway in cancer cells (Ding et al., 2013). G9A, also known as EHMT2 and KMT1C, is a H3K9 methyltransferase that has a primary role in catalyzing H3K9me1 and H3K9me2 in euchromatin (Shinkai and Tachibana, 2011), with H3K9me1 being associated with active chromatin and H3K9me2 being a repressive mark (Black et al., 2012; Mosammaparast and Shi, 2010). We found that G9A is required for maintaining the serine pathway genes in an active state and for transcriptional activation of this pathway in response to serine deprivation. Moreover, higher G9A expression significantly increases serine and glycine biosynthesis in the cell. These findings provide direct evidence for transcriptional reprograming of cell metabolism by a KMT. An implication of the G9A study is that H3K9 methylation states control the transcription of serine pathway genes. This led us to hypothesize that KDMs that target H3K9 may also play a role in transcriptional regulation of the serine pathway. Multiple KDMs catalyze the removal of methyl groups at H3K9: KDM3B can remove all methyl groups (me1-3); KDM4 only me2 and me3; and KDM3A and KDM7A-B only me1 and me2 (Black et al., 2012; Mosammaparast and Shi, 2010). Thus, the KDM4 family of demethylases could transcriptionally activate serine pathway genes by removing the repressive marks H3K9me2 and H3K9me3 at their loci. We focused our study on KDM4C, also known as JMJD2C, primarily because of the strong evidence for an important role of KDM4C in cancer development (Berry and Janknecht, 2013; Labbé et al., 2013). The KDM4C gene is located in chromosome 9p24, which is amplified in various cancer types, including lymphoma, breast cancer, esophageal squamous cell carcinoma, lung sarcomatoid carcinoma, and medulloblastoma (Berdel et al., 2012; Cloos et al., 2006; Ehrbrecht et al., 2006; Italiano et al., 2006; Liu et al., 2009; Northcott et al., 2009; Rui et al., 2010; Vinatzer et al., 2008; Wu et al., 2012; Yang et al., 2000). Our study reveals that KDM4C has a general role in transcriptional activation of amino gamma-Glu-Cys biosynthesis and transport, including serine and glycine. These findings provide evidence for the ability of KDMs to reprogram amino acid metabolism in cancer cells.
    Experimental Procedures
    Author Contributions
    Acknowledgments We thank Dr. Nabieh Ayoub of the Israel Institute of Technology for providing pEGFP-KDM4C-wt and pEGFP-KDM4C-S198M, and Drs. LesleyAnn Hawthorn, Sam Chang, and Eiko Kitamura of the Georgia Regents University Cancer Center Genomics Core for assistance in microarray gene expression profiling. The work was supported by a grant from the National Basic Research Program of China (2012CB114603 to H.C.), grants from the NIH (R01 CA190429 to H.-F.D.) and US Department of Defense (W81XWH-12-1-0613 to H.-F.D.), and a grant from the National Natural Science Foundation of China (81201981 to Y.Z.).
    Introduction Porphyromonas gingivalis, a Gram-negative black-pigmented anaerobe, is a major causative agent of chronic periodontitis [1], which leads to permanent tooth loss [2]. Recently, much attention has been paid to this bacterium and other periodontopathic ‘red complex species’ (Tannerella forsythensis, Treponema denticola) [3], because of their close relationships to systemic diseases, such as atherosclerotic cardiovascular disorder [4–6], decreased kidney function [7], and rheumatoid arthritis [8]. A common feature among these bacteria is that they do not ferment glucose or sucrose (asaccharolytic), but rather utilize amino acids as energy and carbon sources [9–11]. In P. gingivalis, nutritional extracellular proteins are initially degraded to oligopeptides by potent cysteine endopeptidases, i.e., gingipains R (Rgp) and K (Kgp) [12–14], then oligopeptides are degraded to di- and tri-peptides, the main incorporated forms in P. gingivalis[15,16]. As for the amino acid transport system, an analysis of the P. gingivalis genome indicated the existence of two types of oligopeptide transporters [10], which are considered to mediate di- and tri-peptide incorporation. In addition, a sodium ion-driven serine/threonine transporter with a sequence similar to that of the Escherichia coli serine transporter has been reported [17]. In this context, exopeptidases consisting of dipeptidyl peptidases (DPPs), tripeptidyl peptidase, and acylpeptidyl oligopeptidase (AOP) producing di- and tri-peptides from oligopeptides are viewed as important for P. gingivalis to acquire proteinaceous nutrition from the mixed-species environment of the subgingival sulcus.