Impacto de la deficiencia de SWI/SNF en la señalización por TGF-β en cáncer de pulmón

Abstract

SWI/SNF is a family of chromatin remodeling complexes that uses the energy provided by ATP hydrolysis to modify the level of chromatin compaction regulating processes such as gene expression or DNA damage repair. Large cancer sequencing studies have provided evidence of SWI/SNF disruption in 20% of cancer patients, which suggest a tumoral suppressor role of these complexes. However, the molecular mechanisms underlying its role in tumorigenesis remain largely unknown. Lung cancer remains the main cause of cancer-related deaths worldwide with a mean survival rate below 20% despite the new development of targeted or immunotherapies. Consequently, any new knowledge about the molecular mechanisms involved in lung cancer and its potential implication in therapy is a topic of great interest. Morphological changes observed in SWI/SNF-deficient cells made us hypothesize that TGF-β pathway might be affected in these cells due to its function in epithelial-mesenchymal transition (EMT). Here, we analyze the molecular effect of the depletion of a SWI/SNF subunit (ARID2) in several lung cancer cell lines with different mutational backgrounds. Our results suggest that we efficiently produced ARID2 depletion in our cell models using siRNAs. This depletion is accompanied with an alteration of TFG-β pathway evidenced by downregulation of its receptor (TGFBRII). Moreover, this downregulation is not the result of an overactivation of TGF-β signaling, nor by the upregulation of the negative regulator SMAD7; which suggest that SWI/SNF might directly regulate TFGBRII expression. Finally, we have characterized, at the transcriptional level, the response of SWI/SNF deficient cells to TFG-β induction.