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

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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.