Scientists at Dana-Farber Cancer Institute have identified a new protein domain, named SWIFT (SWI/SNF Ig-Fold for Transcription Factor Interactions), located on mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complexes. This discovery reveals how these complexes engage transcription factors (TFs) to target specific genes, including those involved in cancer. The findings were published in Science.
Key Discovery and Mechanism
The SWIFT domain on mSWI/SNF complexes enables them to engage transcription factors (TFs) to activate the expression of particular genes. This interaction helps control the precision and timing of gene expression, which is crucial for normal biological functions. Disruptions in gene expression are linked to various human diseases, including cancers.
Implications for Cancer Therapy
In human cancers, SWIFT-TF engagement supports the expression of cancer-promoting genes and cell growth. Breaking these interactions through mutations has been shown to halt cancer cell growth, suggesting SWIFT-TF interfaces as potential targets for therapeutic development.
Components of mSWI/SNF complexes, specifically SMARCD subunits (SMARCD1, D2, D3), each contain SWIFT domains that bind to different TFs. This explains SMARCD tissue specificity and offers opportunities for targeted therapeutic disruption. Research demonstrated that a single mutation in the SWIFT domain could break the pro-cancer function of the PU.1 transcription factor in blood cancers like acute myeloid leukemia. Additionally, dominant expression of the SWIFT domain in isolation prevented cancer-promoting TFs from binding mSWI/SNF complexes, thereby stopping cancer cell proliferation.
Targeted Therapeutic Approach
mSWI/SNF complexes perform vital functions in normal cells, making systemic targeting problematic due to potential toxicity. Understanding the SWIFT domain, and even subunit-specific SWIFT domains, opens avenues for developing specialized small molecules. These molecules could selectively block specific TF interactions that contribute to cancer and other disease states, allowing for more targeted therapeutic inhibition.
This study was led by Dr. Cigall Kadoch, a professor of pediatric oncology at Dana-Farber, and first author Dr. Siddhant Jain.