# The function of Snf5 (SMARCB1), an epigenetic tumor suppressor

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2021 · $442,391

## Abstract

Project Summary/Abstract:
SMARCB1 (SNF5/INI1/BAF47) is a conserved subunit of SWI/SNF chromatin remodeling complexes, which
utilize the energy of ATP hydrolysis to mobilize nucleosomes. A role for SWI/SNF complexes in cancer was
first suggested when SMARCB1 was identified as inactivated in virtually all cases of malignant rhabdoid tumor
(RT), a highly aggressive pediatric cancer. It has recently been discovered that nearly 25% of all human
malignancies carry mutations in SWI/SNF subunits. We established SMARCB1 to be a bona fide and potent
tumor suppressor and later demonstrated broad epigenetic antagonism between SWI/SNF and Polycomb
repressor complexes during oncogenic transformation. In subsequent work, including substantial progress in
the current funding period, we uncovered novel biological mechanisms and therapeutic vulnerabilities that form
the foundation for the aims described in this proposal. For example, we found that SMARCB1 is essential for
enhancer regulation, thus identifying a new mechanism underlying the tumor-suppressive activity of
SMARCB1. We and others also discovered the existence of a SWI/SNF complex that lacks SMARCB1,
previously considered a core subunit. Instead, this non-canonical complex contains the bromodomain protein
BRD9, which we also identified as a specific vulnerability in SMARCB1-deficient pediatric RTs. While our
findings demonstrate critical interactions of SWI/SNF and Polycomb complexes in transcriptional regulation
and cell fate control, the roles and contributions of SWI/SNF sub-families are unknown. Our first aim is
therefore to determine how SMARCB1-containing SWI/SNF complexes differ from mutually-exclusive BRD9-
containing SWI/SNF complexes in the antagonism of Polycomb interactions and transcriptional regulation.
Recent data from our group have shown that SWI/SNF complexes control histone acetylation and enhancer
function; however, the mechanism by which this leads to a mitotically heritable cancer phenotype is unknown.
Polycomb complexes remain bound to DNA during mitosis, but histone acetylation is erased and the SWI/SNF
ATPase, SMARCA4/BRG1 is phosphorylated and degraded. Thus, for our second aim, we propose to
determine how SWI/SNF complexes contribute to epigenetic memory during mitosis, including interrogating a
potentially paradigm-shifting model that is supported by preliminary data described in this proposal. Finally, we
identified the Polycomb subunit EZH2 as a vulnerability in RTs, inspiring the development of several clinical
trials and leading to recent FDA approval of EZH2 inhibitors for SMARCB1-deficient sarcomas. While
impactful, resistance to these inhibitors has emerged. To establish mechanisms driving drug resistance, we
have performed a near genome-wide CRISPR screen in EZH2 inhibitor-treated RTs, and for our third aim plan
to investigate the mechanism of resistance conferred by mutations in a gene not previously associated with
SWI/SNF functions. Taken together, these questions ...

## Key facts

- **NIH application ID:** 10121044
- **Project number:** 2R01CA113794-17A1
- **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:** $442,391
- **Award type:** 2
- **Project period:** 2005-07-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10121044

## Citation

> US National Institutes of Health, RePORTER application 10121044, The function of Snf5 (SMARCB1), an epigenetic tumor suppressor (2R01CA113794-17A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10121044. Licensed CC0.

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