title: The histone H3 methyltransferase G9A epigenetically activates the serine-glycine synthesis pathway to sustain cancer cell survival and proliferation.
abstract: Increased activation of the serine-glycine biosynthetic pathway is an integral part of cancer metabolism that drives macromolecule synthesis needed for cell proliferation. Whether this pathway is under epigenetic control is unknown. Here we show that the histone H3 lysine 9 (H3K9) methyltransferase G9A is required for maintaining the pathway enzyme genes in an active state marked by H3K9 monomethylation and for the transcriptional activation of this pathway in response to serine deprivation. G9A inactivation depletes serine and its downstream metabolites, triggering cell death with autophagy in cancer cell lines of different tissue origins. Higher G9A expression, which is observed in various cancers and is associated with greater mortality in cancer patients, increases serine production and enhances the proliferation and tumorigenicity of cancer cells. These findings identify a G9A-dependent epigenetic program in the control of cancer metabolism, providing a rationale for G9A inhibition as a therapeutic strategy for cancer.
authors: Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors: Jane
authors: J
authors: Ding
authors: Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.|State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and System Biology, Southwest University, Chongqing 400716, China.
authors: Tai
authors: T
authors: Li
authors: Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing 400037, China.
authors: Xiangwei
authors: X
authors: Wang
authors: Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.|State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and System Biology, Southwest University, Chongqing 400716, China.
authors: Erhu
authors: E
authors: Zhao
authors: Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.|Department of Biostatistics and Epidemiology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors: Jeong-Hyeon
authors: JH
authors: Choi
authors: State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and System Biology, Southwest University, Chongqing 400716, China.
authors: Liqun
authors: L
authors: Yang
authors: Department of Neurology, The First Hospital of Yichang, Three Gorges University College of Medicine, Yichang 423000, China.
authors: Yunhong
authors: Y
authors: Zha
authors: Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors: Zheng
authors: Z
authors: Dong
authors: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors: Shuang
authors: S
authors: Huang
authors: Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors: John M
authors: JM
authors: Asara
authors: State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and System Biology, Southwest University, Chongqing 400716, China.
authors: Hongjuan
authors: H
authors: Cui
authors: Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.|Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.|Department of Pathology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors: Han-Fei
authors: HF
authors: Ding
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D057890:Epigenomics; D005998:Glycine / Q000096:biosynthesis*; D006367:HeLa Cells; D006649:Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D012270:Ribosomes / Q000378:metabolism; D012694:Serine / Q000096:biosynthesis* / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D001381:Azepines; C518299:BIX 01294; D006649:Histocompatibility Antigens; D006657:Histones; C502070:MAP1LC3B protein, human; D008869:Microtubule-Associated Proteins; D011799:Quinazolines; D012694:Serine; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase; D005998:Glycine