# CCAR2 as a Target for Prevention of Colorectal Cancer.

> **NIH NIH R01** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2020 · $602,919

## Abstract

Cell Cycle and Apoptosis Regulator Protein 2 (CCAR2) is overexpressed in human colorectal cancer and is
associated with poor prognosis, due in part to its role as a coactivator of -catenin-dependent transcription.
The dietary preventive agent sulforaphane (SFN) targets CCAR2 interacting protein histone deacetylase 3
(HDAC3) for inhibition, resulting in acetylation of CCAR2, reduced CCAR2/-catenin nuclear interactions, and
attenuated -catenin-dependent transcription. The novel CCAR2 acetylation sites align with a domain linked to
S1 RNA binding, providing a new mechanistic link to alternative RNA splicing by SFN and other dietary isothio-
cyanates (ITCs). Using novel protein domain arrays, bromodomain-containing proteins were identified that
recognized acetylated forms of CCAR2. These acetyl “readers” also were inhibited by JQ1, which binds to
bromodomain and extraterminal (BET) family proteins, and synergized with SFN to inhibit cell viability in colon
cancer cells. CENTRAL HYPOTHESIS: In the prevention of colon cancer by dietary ITCs and mechanistically-
prioritized drug combinations, HDAC3 inhibition leads to acetylation of CCAR2 and changes in protein-protein
interactions that enhance apoptosis via the inhibition of -catenin-dependent transcription and via altered RNA
splicing. Aim 1a: Test the hypothesis that by inhibiting HDAC3, ITCs alter the acetylation status of CCAR2 in
colon cancer cells, with consequences for -catenin signaling and apoptosis induction. Aim 1b: Perform
mechanistic studies on the acetyl readers of CCAR2, and test inhibitors of readers that synergize with SFN.
Aim 1c: Examine the role of CCAR2 and the DBIRD complex in RNA splicing. Aim 2a: Using the polyposis in
rat colon (Pirc) model, extend to working hypothesis in vivo linking HDAC3 inhibition, CCAR2 acetylation,
reduced -catenin signaling and apoptosis induction. Single acute doses of SFN, 6-SFN and 9-SFN will be
tested alone and in combination with JQ1. The most effective agents from Aim 2a will be assessed for tumor
suppression in the Pirc model via primary (Aim 2b) and secondary prevention protocols (Aim 2c). Using
sequential endoscopy and polyp resection in live rats, define the precise timing of HDAC3 protein loss, CCAR2
acetylation, reduced nuclear CCAR2/-catenin interactions, and the downregulation of -catenin targets. Aim
2d: Extend mechanistic studies from Aim 1c linking CCAR2 acetylation to alternative RNA splicing after ITC
treatment into the Pirc model. Aim 3a: In biopsies from FAP patients, establish the translational relevance of
findings in the Pirc model with respect to CCAR2 overexpression and its interactions with -catenin, HDAC3,
and ZIRD. Aim 3b: In colonoids from Pirc and FAP patients, test the hypothesis that SFN, 6-SFN and 9-SFN
alter the acetylation status of CCAR2 and its protein-protein interactions, with consequences for -catenin
signaling and apoptosis induction. Test individual ITCs and their combinations with JQ1. Aim 3c: In nud...

## Key facts

- **NIH application ID:** 9873928
- **Project number:** 5R01CA122959-08
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **Principal Investigator:** Roderick H Dashwood
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $602,919
- **Award type:** 5
- **Project period:** 2008-04-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873928

## Citation

> US National Institutes of Health, RePORTER application 9873928, CCAR2 as a Target for Prevention of Colorectal Cancer. (5R01CA122959-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9873928. Licensed CC0.

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