Identification of molecular targets of SWI/SNF alterations in cancer development
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AuthorMonterde Martínez, Beatriz
SWI/SNF chromatin remodelling complex has been described to be altered in nearly 20 % of all human tumour types, which places it among the most broadly mutated molecular systems in human cancer, just after TP53. However, the molecular mechanism underlying its involvement in tumour progression remains elusive. Among the different subunits of the complex, ARID1A has been identified as one of the most frequently mutated genes in several human malignancies, such as gynaecological and intestinal tumours. Therefore, the main purpose of this Master’s thesis is to get a further insight into the transcriptional alterations resulted from ARID1A-deficiency in different cellular contexts. In order to achieve this goal, we have generated stably-transduced cell lines for a doxycyclineinducible vector that directs the expression of different shRNAs targeting ARID1A in different human cancer cell lines. After the verification of an effective ARID1A knock-down, RNA-Seq experiments revealed both shared and tissue specific molecular pathways altered in the different cell lines. Among them, it should be highlighted an upregulation of genes belonging to proliferative pathways, as well as a downregulation of genes involved in apoptosis, which suggests an augmentation in their oncogenic capacities. What is more, there was also an upregulation of genes involved in cell migration, which might imply a potential increase in their metastatic capacities. Finally, gene set enrichment analyses showed a significant upregulation of genes related to the immune response. These results might help to clarify the molecular pathways underlying the role of ARID1A alteration in tumour progression and they could also suggest new therapeutic opportunities for SWI/SNF-deficient tumours.