Document text
Principal Investigator: Qing Zhang
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2024
Award: $406,336
Funding agency: National Cancer Institute
Project Summary
Distinct histone modifications, on N or C-terminal tails, act as a “histone code” to elicit downstream events.
Histone subunit post-translational modification (PTM), such as methylation, acetylation and phosphorylation
regulates epigenetic regulation and gene expression in diseases such as cancer. Here we identified a new PTM
on H3 called hydroxylation on proline 16, which is catalyzed by proline hydroxylase EglN2. Our preliminary data
show that EglN2-mediated H3 Pro16-OH leads to increased Lysine (K)-Specific Demethylase 5A (KDM5A)
binding corresponding with decreased H3K4me3 in breast cancer. We hypothesize that H3 prolyl hydroxylation
mediated by EglN2 recruits KDM5A therefore controlling gene expression important in breast cancer.
This is the first study reporting H3 Prolyl hydroxylation and its potential role in epigenetic regulation and gene
expression in cancer. In Specific Aim 1, we will determine the effet of H3 prolyl hydroxylation on epigenetic
regulation and gene expression on a genome wide scale in breast cancer cells. In Specific Aim 2, we will
elucidate the molecular mechanism by which H3 prolyl hydroxylation regulates epigenetic reprogramming by
recruiting KDM5A. In Specific Aim 3, we will elucidate the molecular mechanism by which H3 prolyl hydroxylation
regulates Wnt/b-Catenin signaling in breast cancer cells. Successful completion of this proposal will characterize
a new H3 post-translational modification in its epigenetic regulation and gene expression important in breast
cancer.
Terms: <ARNT><ARNT gene><Acetylation><Affect><Antibodies><Aryl Hydrocarbon Receptor Nuclear Translocator><Beta Cadherin-Associated Protein><Beta-1 Catenin><Binding><Breast Cancer><Breast Cancer Cell><Breast Cancer Patient><Breast Cancer cell line><Breast Epithelial Cells><Breast Tumor Patient><Breast tumor cell line><C-terminal><CUL-2><CUT&RUN><Cancers><Cell Body><Cell Communication and Signaling><Cell Growth Inhibitors><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Signaling><Cells><Cellular Proliferation><Characteristics><Cleavage Targets and Release Using Nuclease><Cleavage Under Targets and Release Using Nuclease><Complex><Data><Detection><Dimerization><Dioxin Receptor, Nuclear Translocator><Disease><Disorder><E3 Ligase><E3 Ubiquitin Ligase><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Event><Family member><Gene Action Regulation><Gene Expression><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Transcription><Genes><Genetic Transcription><Genomics><Growth Inhibitors><HIF-1 Beta Gene><HIF-1Beta Gene><HIF-1beta><HIF1-Beta Gene><HIF1B><HIF1B Gene><HIF1Beta><HIF1beta Gene><Histone Code><Histone H3><Histones><Hydroxylation><Hypoxia><Hypoxia Inducible Factor><Hypoxia-Inducible Factor 1 Beta Gene><Hypoxia-Inducible Factor 1, Beta subunit><Hypoxic><Immunoblotting><In Vitro><Intermediary Metabolism><Intracellular Communication and Signaling><L-Lysine><L-Proline><Lead><Lysine><MLL leukemia><Malignant><Malignant - descriptor><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Measures><Mediating><Metabolic Processes><Metabolism><Methylation><Mixed-Lineage Leukemia><Modeling><Modification><Molecular><Molecular Interaction><Nuclear Translocator Gene Dioxin Receptor><O element><O2 element><Oncogenesis><Oncogenic><Oxygen><Oxygen Deficiency><PRO2286><Pb element><Peptidyl Prolyl Hydroxylase><Phosphorylation><Play><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Procollagen Prolyl 4-Hydroxylase><Procollagen-Proline Dioxygenase><Proline><Proline Hydroxylase><Proline,2-Oxoglutarate 4-Dioxygenase><Prolyl 4-Hydroxylase><Prolyl Hydroxylase><Protein Dimerization><Protein Modification><Protein Phosphorylation><Proteins><Protocollagen Prolyl Hydroxylase><RNA Expression><Reader><Reporting><Repression><Role><Signal Transduction><Signal Transduction Systems><Signaling><Solid><TANGO><TNBC><Tail><Transcription><Ubiquitilation><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><Ubiquitination><Ubiquitinoylation><WNT Signaling Pathway><WNT signaling><Western Blotting><Western Immunoblotting><Writing><angiogenesis><beta catenin><biological signal transduction><breast tumor cell><cancer cell><clinical relevance><clinically relevant><demethylation><epigenetic regulation><epigenetically><genome scale><genome-wide><genomewide><heavy metal Pb><heavy metal lead><histone demethylase><histone modification><in vivo><inhibitor><insight><malignancy><malignant breast tumor><mammary epithelial cells><neoplasm/cancer><novel><promoter><promotor><protein blotting><recruit><social role><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumorigenesis><ubiquination><ubiquitin conjugation><ubiquitin-protein ligase><β-catenin>