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

> **NIH NIH P20** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2024 · $280,905

## Abstract

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.

## Key facts

- **NIH application ID:** 10986969
- **Project number:** 5P20GM121316-07
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Kurt Fisher
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $280,905
- **Award type:** 5
- **Project period:** 2018-03-16 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10986969

## Citation

> US National Institutes of Health, RePORTER application 10986969, Novel Mechanisms of Inhibiting Transcriptional Coactivators for Anti-Cancer Therapy in Colorectal Cancer (5P20GM121316-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10986969. Licensed CC0.

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