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Novel Mechanisms of Inhibiting Transcriptional Coactivators for Anti-Cancer Therapy in Colorectal Cancer

抑制转录辅激活因子用于结直肠癌抗癌治疗的新机制

基本信息

批准号：
10937171
负责人：
Kurt Fisher
金额：
$ 21.07万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-28 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10937171
关键词：
Binding Binding Proteins Cells Clustered Regularly Interspaced Short Palindromic Repeats Colorectal Cancer DNA sequencing Data Development Disease Epigenetic Process Gene Expression Genes Genetic Transcription Genomics Goals Growth Histone-Lysine N-Methyltransferase Homeostasis Immunoprecipitation Injections KRAS2 gene Mass Spectrum Analysis Metabolism Metastatic Neoplasm to the Liver Modeling Molecular Biology Molecular Target Mutation Nebraska Organoids PPAR gamma Patients Protein Family Proteins Submucosa Testing Transcription Coactivator Transcription Initiation anti-cancer cancer therapy histone methyltransferase imprint in vivo evaluation inhibitor loss of function metastatic colorectal mutant neoplastic cell novel overexpression prevent promoter protein protein interaction therapeutic target transcription factor tumor

项目摘要

PGC-1 family proteins (PGC-1á, PGC-1â, and PPRC1) are transcriptional co-activators that act as central hubs to coordinate diverse cellular inputs to promote the transcription of genes that regulate metabolism to maintain homeostasis. Transcriptional coactivator Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1 â (PGC-1â) is over-expressed in colorectal cancers (CRC) with K-Ras mutations and promotes the survival of tumor cells. PGC-1 family proteins lack intrinsic enzymatic activity and function by facilitating interactions between transcription factors, epigenetic modifiers, and transcription initiation machinery. To identify the protein-protein interactions required by PGC-1â to coordinate gene expression we immunoprecipitated PGC-1â and identified binding partners by mass spectrometry. Our data reveal that Host Cell Factor 2 (HCF2) is a PGC-1â binding protein that we propose is required to bring PGC-1â to the proximal promoter and imprint epigenetic marks that promote transcription. Our long-term goal is to inhibit CRC growth by blocking the interaction of PGC-1â with HCF2 or by blocking the interaction of HCF2 with histone lysine methyltransferase SEDT1A, which is required to enhance PGC-1â-dependent gene expression. In Aim 1, we will define the motifs required for HCF2 to bind PGC-1â and SETD1A and assess the loss of function of HCF2 binding mutants in PGC-1â-dependent gene expression and genomic localization. In Aim 2, we will test the loss of the PGC-1â-HCF2 interaction and the loss of the HCF2- SETD1A interaction in patient-derived tumor organoids establish from liver metastases in an orthotopic submucosal injection model.

PGC-1家族蛋白（PGC-1 <e:1>、pgc - 1<e:2>和PPRC1）是转录共激活因子，作为中心激活因子