Epigenetic regulation of cancer metabolism by G9A

Project: Research projectResearch Project

Description

DESCRIPTION (provided by applicant): Cancer cells reprogram their metabolism to meet the biosynthetic challenge of growth and proliferation. How cancer metabolism is initiated and maintained in cancer cells is a central question of cancer research. Recent studies demonstrate that increased activation of the serine-glycine synthesis pathway, which generates many biosynthetic precursors and metabolites essential for the production of proteins, lipid membranes and nucleic acids, is an integral part of cancer metabolism. We recently uncovered an essential role of the histone H3 lysine 9 (H3K9) methyltransferase G9A in epigenetic activation of this biosynthesis pathway. G9A has a primary role in catalyzing H3K9 monomethylation and dimethylation (H3K9me1 and H3K9me2), with H3K9me1 being an active mark and H3K9me2 being a repressive mark. G9A overexpression has been observed in many types of human cancers. We found that G9A transcriptionally activates serine-glycine synthesis by increasing H3K9me1 at the promoters of the pathway genes. The proposed research is to determine 1) how G9A is specifically targeted to the pathway genes, given that G9A has no sequence-specific DNA-binding domain, and 2) how G9A specifically marks these genes with H3K9me1, given that G9A can catalyze both H3K9me1 and H3K9me2. In Aim 1, we will investigate the sequence-specific DNA-binding transcription factor ATF4 as a mechanism for targeting G9A to the promoters of the serine pathway genes. We will determine whether ATF4 is required for G9A to bind to these promoters, to modulate their H3K9 methylation states, and to increase glycolic flux for serine-glycine synthesis. We will also investigate the molecular basis o the G9A-ATF4 interaction. In Aim 2, we will investigate the transcription factor MYCN as an alternative mechanism for targeting G9A to the serine pathway genes, particularly in cancer cells with G9A overexpression. We will determine whether MYCN is required for G9A to bind to these gene promoters, to modulate their H3K9 methylation states, and to increase glycolic flux for serine-glycine synthesis. We will also investigate the molecular basis of the G9A-MYCN interaction. In Aim 3, we will test the hypothesis that the H3K9 demethylase KDM4C, which specifically removes H3K9me2 and H3K9me3, cooperates with G9A to maintain high levels of H3K9me1 at these gene promoters. We will determine whether G9A and KDM4C bind simultaneously to these gene promoters and whether G9A requires KDM4C to maintain high-level H3K9me1 at these promoters for transcriptional activation. We will also investigate the molecular basis of the G9A-KDM4C cooperation. The proposed investigation is anticipated to identify a new regulatory mechanism for the control of serine-glycine synthesis and to introduce a new avenue to target cancer metabolism for therapy. Additionally, functional assays of
StatusActive
Effective start/end date9/15/148/31/19

Funding

  • National Institutes of Health: $313,671.00
  • National Institutes of Health: $315,400.00

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Epigenomics
Serine
Glycine
Genes
Neoplasms
Methylation
Activating Transcription Factor 4
Methyltransferases
Membrane Lipids
Research
Histones
Nucleic Acids
Transcriptional Activation
Lysine
Membrane Proteins
Transcription Factors
Growth

Keywords

  • Medicine(all)