Chromatin remodeling complexes are crucial for the viability of the cells due to their role in regulating interactions between DNA and histones and, therefore, modifying the accessibility of the genetic information to the transcriptional machinery. This relevance can also been seen in the SWI/SNF complex that has been associated with cancer in the last deep-sequencing efforts on tumoral genomes.
BRG1 is the helicase/ATPase catalytic subunit of the SWI/SNF complex and it is frequently lost in NSCLC cell lines with a high mutation rate. In primary tumors, the loss of expression of BRG1 is also frequent, however it cannot be explained by mutations or by promoter hypermethylation.
In this study we have focused on the regulation of the expression of BRG1 by microRNAs. These are small RNA molecules that do not code for any protein but they have key roles in gene expression regulation by binding to the 3’UTR of the transcripts. In addition, their levels have been found altered in several diseases including cancer. Our hypothesis is that the deregulation observed in BRG1 levels in primary tumors can be associated with changes in the microRNAs that control its expression.
We have studied the 3’UTR of BRG1 by performing a Rapid Amplification of 3’ cDNA Ends (3’ RACE) and we have cloned the resulting 3’UTRs after a luciferase coding sequence of a plasmid in other to use the luminescence signal as a method to analyze the binding of the microRNAs tested to the 3’UTR of BRG1. Previous bioinformatic analyses were performed to choose the best microRNAs that could potentially regulate BRG1.
Our preliminary results indicate that some microRNAs are able to bind to the 3’UTRs and successfully repress the expression of catalytic subunit of SWI/SNF. Importantly, one of these microRNAs is well known for developing oncogenic activities in lung cancer and it has been related with poor prognosis.
In conclusion, the activity of the SWI/SNF complex can be regulated by microRNAs and this regulation may be relevant during lung carcinogenesis. From the other perspective, SWI/SNF complex could also impact in lung carcinogenesis regulating microRNAs expression, an aspect that we are currently evaluating.
Citation Format: Paola Peinado Fernández, Isabel Fernández Coira, Eva E. Rufino Palomares, Octavio A. Romero, Chanatip Metheetrairut, Laura Boyero Corral, Julián Carretero, Esther Farez Vidal, Marta Cuadros Celorrio, Fernando Reyes Zurita, Victoria Sánchez Martín, Carlos Baliñas Gavira, Jose A. Lupiáñez Cara, Montse Sánchez Céspedes, Frank Slack, Pedro P. Medina. Unveiling the relationship between the SWI/SNF chromatin remodeling complex and noncoding RNAs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4479.