SWI/SNF Complex Dysregulation in Cancer

The SWI/SNF (SWItch/Sucrose Non-Fermentable) family of ATP-dependent chromatin remodelling complexes plays a pivotal role in orchestrating gene expression programmes that govern cell differentiation, proliferation and DNA repair. In diverse human cancers, genetic and epigenetic alterations of SWI/SNF subunits—most notably ARID1A, SMARCA4, SMARCB1 and PBRM1—are among the most frequent mutational events. Loss-of-function mutations in these subunits commonly disrupt nucleosome positioning at enhancers and promoters, impair tumour-suppressive gene networks and deregulate chromatin accessibility. Paradoxically, in certain cellular contexts residual SWI/SNF complexes can acquire oncogenic functions, sustaining tumour cell survival and therapy resistance. Emerging evidence reveals that subunit deficiencies create vulnerabilities to synthetic lethal interactions, whereby inhibition of a paralogue or a cooperating chromatin regulator selectively kills SWI/SNF-deficient cells. These insights into the dualistic tumour-suppressor and context-dependent oncogenic roles of SWI/SNF dysregulation have spurred efforts to exploit chromatin remodelling dependencies for precision oncology and have underscored the global significance of SWI/SNF biology across malignancies of adult and paediatric origin.

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Technical terms

SWI/SNF complex: Multisubunit ATP-dependent chromatin remodeller that repositions nucleosomes to regulate gene accessibility.

Chromatin remodelling: Dynamic alteration of nucleosome arrangement to modulate DNA accessibility for transcription and repair.

Subunit: Individual protein component of a larger multiprotein complex.

Synthetic lethality: A genetic interaction where simultaneous perturbation of two genes leads to cell death, whereas each alone is tolerated.

Tumour suppressor: Gene or protein that prevents uncontrolled cell growth; its loss promotes oncogenesis.

Oncogene: Gene or protein whose activation or overexpression drives cancer development.

Enhancer: Distal regulatory DNA element that increases transcription of associated genes through chromatin looping.

ATPase: Enzymatic subunit that hydrolyses ATP to power conformational changes in the remodelled complex.

References

1. SWI/SNF complexes in hematological malignancies: biological implications and therapeutic opportunities. Molecular Cancer (2023).
2. Transcriptional-translational conflict is a barrier to cellular transformation and cancer progression. Cancer Cell (2023).
3. The Spectrum of SWI/SNF Mutations, Ubiquitous in Human Cancers. PLOS ONE (2013).
4. The SWI/SNF chromatin remodelling complex is required for maintenance of lineage specific enhancers. Nature Communications (2017).
5. Chromatin accessibility underlies synthetic lethality of SWI/SNF subunits in ARID1A-mutant cancers. eLife (2017).