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Emerging Themes in Mechanisms of Tumorigenesis by SWI/SNF Subunit Mutation
Cheyenne A Jones1, William P Tansey2,3, April M Weissmiller1
1Department of Biology, Middle Tennessee State University, Murfreesboro, TN, USA.
Abstract:
The SWI/SNF chromatin remodeling complex uses the energy of ATP hydrolysis to alter contacts between DNA and nucleosomes, allowing regions of the genome to become accessible for biological processes such as transcription. The SWI/SNF chromatin remodeler is also one of the most frequently altered protein complexes in cancer, with upwards of 20% of all cancers carrying mutations in a SWI/SNF subunit. Intense studies over the last decade have probed the molecular events associated with SWI/SNF dysfunction in cancer and common themes are beginning to emerge in how tumor-associated SWI/SNF mutations promote malignancy. In this review, we summarize current understanding of SWI/SNF complexes, their alterations in cancer, and what is known about the impact of these mutations on tumor-relevant transcriptional events. We discuss how enhancer dysregulation is a common theme in SWI/SNF mutant cancers and describe how resultant alterations in enhancer and super-enhancer activity conspire to block development and differentiation while promoting stemness and self-renewal. We also identify a second emerging theme in which SWI/SNF perturbations intersect with potent oncoprotein transcription factors AP-1 and MYC to drive malignant transcriptional programs.
Insights
SWI/SNF chromatin remodelers are frequently mutated in cancer. These mutations disrupt gene regulation by altering enhancers and interacting with oncoproteins, promoting cancer stemness and malignancy.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Biology
Background:
- The SWI/SNF complex remodels chromatin using ATP hydrolysis, regulating DNA accessibility for transcription.
- SWI/SNF is frequently altered in over 20% of human cancers, indicating its critical role in malignancy.
- Recent research has focused on understanding how SWI/SNF dysfunction drives cancer progression.
Purpose of the Study:
- To review the current understanding of SWI/SNF complexes and their alterations in cancer.
- To summarize the impact of SWI/SNF mutations on tumor-associated transcriptional events.
- To highlight emerging themes in SWI/SNF-driven oncogenesis.
Main Methods:
- Literature review of studies on SWI/SNF complex function, cancer mutations, and transcriptional regulation.
- Analysis of common mechanisms by which SWI/SNF mutations promote malignancy.
- Synthesis of current knowledge on enhancer dysregulation and oncoprotein interactions in SWI/SNF mutant cancers.
Main Results:
- SWI/SNF mutations commonly lead to enhancer and super-enhancer dysregulation.
- Altered enhancer activity in SWI/SNF mutant cancers promotes stemness and self-renewal, hindering differentiation.
- SWI/SNF perturbations cooperate with AP-1 and MYC oncoproteins to drive malignant transcriptional programs.
Conclusions:
- Dysregulation of enhancers is a key mechanism through which SWI/SNF mutations promote cancer.
- The interplay between SWI/SNF, AP-1, and MYC is crucial for driving oncogenic transcriptional programs.
- Understanding these mechanisms offers potential therapeutic strategies for SWI/SNF-mutant cancers.
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