# Role of the SWI/SNF complex in tumor suppression

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2021 · $399,004

## Abstract

Project Summary/Abstract:
Cancer genome sequencing studies have now revealed that genes that encode nine different subunits of
SWI/SNF chromatin remodeling complexes are frequently mutated in a wide variety of human cancers. These
include cancers of brain, ovary, breast, kidney, lung, pancreas, uterus, bladder, stomach, colon, liver, skin and
blood. Collectively, over twenty percent of all human cancers contain a SWI/SNF mutation making SWI/SNF
complexes the most frequently mutated chromatin/epigenetic regulator in cancer. During the current funding
cycle we have made notable progress in elucidating the functions of SWI/SNF complexes. However, major
questions have subsequently emerged. SWI/SNF complexes consist of both core subunits and variant subunits,
with the latter present in only sub-classes of complexes. It has now become clear that the frequently mutated
subunits are all variant subunits including ARID1A, SMARCA4 and PBRM1 and that mutation of each is
associated with a distinct cancer spectrum. However, the mechanistic and functional contributions of these
variant subunits and sub-classes to SWI/SNF function is poorly understood. We hypothesize that oncogenesis
occurs not due to broad loss of SWI/SNF complex function but rather due to aberrant function of residual
SWI/SNF complexes. We further hypothesize that loss of the variant tumor-suppressor subunits alters the
composition, targeting and chromatin remodeling activity of SWI/SNF thus impairing differentiation and
promoting oncogenesis. Using our genetically engineered primary cells, cell lines and mice, we will address
three aims: Aim 1: How do the mutually exclusive ATPase subunits of SWI/SNF complexes, SMARCA4/BRG1
and SMARCA2/BRM, differ in function and what is the mechanistic basis for the synthetic lethality of SMARCA2
in SMARCA4 mutant cancers? Aim 2: How does the PBRM1-containig PBAF sub-class of SWI/SNF complexes
differ from the ARID1A/B-containing BAF sub-class with respect to composition, targeting, chromatin remodeling
activity, enhancer regulation and control of lineage specification? Aim 3: How does our newly discovered BRD9-
containing sub-class differ in composition and function from other SWI/SNF sub-classes, and can BRD9 be
exploited as a therapeutic target?

## Key facts

- **NIH application ID:** 10248410
- **Project number:** 5R01CA172152-10
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** CHARLES ROBERTS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $399,004
- **Award type:** 5
- **Project period:** 2013-07-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10248410

## Citation

> US National Institutes of Health, RePORTER application 10248410, Role of the SWI/SNF complex in tumor suppression (5R01CA172152-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10248410. Licensed CC0.

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