SMARCA4 Inhibits Breast Tumor progression through Transcriptional Activation of GTPase Activating Factor ARHGAP29 and RHOA Suppression [ATAC]
The chromatin-remodeling SWI/SNF complex emerged as a potent suppressor of tumor spheroid growth. SMARCA4 was identified as a top candidate to suppress TNBC growth in 3D tumor spheroid model using genome-wide CRISPR screen. Specifically, the loss of the SWI/SNF ATPase subunit SMARCA4 promotes tumor spheroid growth with reduced compactness, and enhanced the growth in breast primary tumors and metastasis across multiple breast cancer models. Further investigations revealed its function in inhibiting the RHOA pathway. SMARCA4 is required for the transcription of Rho GTPase activating factor ARHGAP29, achieved through direct binding to its promoter to provide DNA accessibility. The loss of SMARCA4 resulted in reduced ARHGAP29 levels and hyperactive RHOA signaling. This subsequently disrupted cell adhesion, facilitated a loose spheroid structure and promoted spheroid growth. Overall design: Whole genome chromatin accessibility profiles for SMARCA4 manipulated derivatives of TNBC SUM159 cells were determined using ATACseq. The panel of 4 derivative samples include NTC (non-targeting control), KD1 (SMARCA4 knockdown), KD1+SMARCA4 (rescue) and KD1+Vec (rescue control)