The SWI/SNF complex regulates the expression of miR-222, a tumor suppressor microRNA in lung adenocarcinoma

SWI/SNF chromatin remodeling complexes are key epigenetic regulators that are recurrently mutated in cancer. Most studies of these complexes are focused on their role in regulating protein-coding genes. However, here we show that SWI/SNF complexes control the expression of microRNAs. We used a SMARCA4-deficient model of lung adenocarcinoma (LUAD) to track changes in the miRNome upon SMARCA4 restoration. We found that SMARCA4-SWI/SNF complexes induced significant changes in the expression of cancer-related microRNAs. The most significantly dysregulated microRNA was miR-222, whose expression was promoted by SMARCA4-SWI/SNF complexes but not by SMARCA2-SWI/SNF complexes via their direct binding to a miR-222 enhancer region. Importantly, miR-222 expression decreased cell viability, phenocopying the tumor-suppressor role of SMARCA4-SWI/SNF complexes in LUAD. Finally, we showed that the miR-222 enhancer region resides in a topologically associated domain that does not contain any cancer-related protein-coding genes, suggesting that miR-222 may be involved in exerting the tumor suppressor role of SMARCA4. Overall, this study highlights the relevant role of the SWI/SNF complex in regulating the non-coding genome, opening new insights into the pathogenesis of LUAD.