SMARCA4, also known as BRG1 (Brahma-related gene 1), is a core ATPase subunit of the SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complex. This complex is evolutionarily conserved and plays a crucial role in regulating gene transcription, DNA repair, differentiation, and development by mobilizing nucleosomes .
SMARCA4 is an ATP-dependent chromatin remodeling enzyme that modulates nucleosome positioning and structure. It is essential for the regulation of transcription through the control of chromatin structure. The SWI/SNF complex, which includes SMARCA4, facilitates the access of transcription factors to DNA by altering the chromatin landscape .
SMARCA4 functions as a tumor suppressor and is implicated in various human malignancies. Alterations in the SMARCA4 gene, such as truncating mutations, fusions, and homozygous deletions, lead to loss of function and are associated with several cancers, including lung, colon, bladder, and breast carcinomas . These alterations can result in either loss-of-function or gain-of-function effects, contributing to cancer development and progression .
SMARCA4 alterations are particularly significant in certain rare cancers, such as small cell carcinomas of the ovary hypercalcemic type (SCCOHT) and SMARCA4-deficient thoracic and uterine sarcomas . Germline variants in the SMARCA4 gene are linked to hereditary conditions like rhabdoid tumor predisposition syndrome-2 (RTPS2) and Coffin-Siris syndrome . These conditions are characterized by aggressive tumors and developmental delays, respectively.
Research into therapeutic strategies targeting SMARCA4-altered cancers is ongoing. Immune checkpoint blockade has shown promising responses in SCCOHT . Additionally, inhibitors targeting BET, EZH2, HDAC, CDK4/6, and FGFR, as well as agents inducing synthetic lethality via DNA damage repair impairment, are being explored .