ARID2 deficiency promotes tumor progression and is associated with higher sensitivity to chemotherapy in lung cancer
Thaidy Moreno-Rodriguez, Beatriz Monterde, Laura González-Silva, Isabel Betancor-Fernández, Carlos Revilla, Antonio Agraz-Doblás, Javier Freire, Pablo Isidro, Laura Quevedo, Rosa Blanco, Santiago Montes‐Moreno, Laura Cereceda, Aurora Astudillo, Berta Casar, Piero Crespo, Cristina Morales, Paola Scaffidi, Javier Gómez‐Román, Eduardo Salido, Ignacio Varela
Abstract
The survival rate in lung cancer remains stubbornly low and there is an urgent need for the identification of new therapeutic targets. In the last decade, several members of the SWI/SNF chromatin remodeling complexes have been described altered in different tumor types. Nevertheless, the precise mechanisms of their impact on cancer progression, as well as the application of this knowledge to cancer patient management are largely unknown. In this study, we performed targeted sequencing of a cohort of lung cancer patients on genes involved in chromatin structure. In addition, we studied at the protein level the expression of these genes in cancer samples and performed functional experiments to identify the molecular mechanisms linking alterations of chromatin remodeling genes and tumor development. Remarkably, we found that 20% of lung cancer patients show ARID2 protein loss, partially explained by the presence of ARID2 mutations. In addition, we showed that ARID2 deficiency provokes profound chromatin structural changes altering cell transcriptional programs, which bolsters the proliferative and metastatic potential of the cells both in vitro and in vivo. Moreover, we demonstrated that ARID2 deficiency impairs DNA repair, enhancing the sensitivity of the cells to DNA-damaging agents. Our findings support that ARID2 is a bona fide tumor suppressor gene in lung cancer that may be exploited therapeutically.