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. Additionally, 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. Additionally, we showed that ARID2-deficiency provokes profound chromatin structural changes altering cell transcriptional programmes 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.
Correct B cell identity at each stage of cellular differentiation during B lymphocyte development is critically dependent on a tightly controlled epigenomic landscape. We previously identified HDAC7 as an essential regulator of early B cell development and its absence leads to a drastic block at the pro-B to pre-B cell transition. More recently, we demonstrated that HDAC7 loss in pro-B-ALL in infants associates with a worse prognosis. Here we delineate the molecular mechanisms by which HDAC7 modulates early B cell development. We find that HDAC7 deficiency drives global chromatin de-condensation, histone marks deposition and deregulates other epigenetic regulators and mobile elements. Specifically, the absence of HDAC7 induces TET2 expression, which promotes DNA 5-hydroxymethylation and chromatin de-condensation. HDAC7 deficiency also results in the aberrant expression of microRNAs and LINE-1 transposable elements. These findings shed light on the mechanisms by which HDAC7 loss or misregulation may lead to B cell–based hematological malignancies.
SWI/SNF family of chromatin remodeling complexes uses the energy of ATP to change the structure of DNA, playing key roles in DNA regulation and repair. It is estimated that up to 25% of all human cancers contain alterations in SWI/SNF, although the precise molecular mechanisms for their involvement in tumor progression are largely unknown. Despite the improvements achieved in the last decades on our knowledge of lung cancer molecular biology, it remains the major cause of cancer-related deaths worldwide and it is in urgent need for new therapeutic alternatives. We and others have described recurrent alterations in different SWI/SNF genes in nearly 20% of lung cancer patients, some of them with a significant association with worse prognosis, indicating an important role of SWI/SNF in this fatal disease. These alterations might be therapeutically exploited, as it has been shown in cellular and animal models with the use of EGFR inhibitors, DNA-damaging agents and several immunotherapy approaches. Therefore, a better knowledge of the molecular mechanisms regulated by SWI/SNF alterations in lung cancer might be translated into a therapeutic improvement of this frequently lethal disease. In this review, we summarize all the evidence of SWI/SNF alterations in lung cancer, the current knowledge about the potential mechanisms involved in their tumorigenic role, as well as the results that support a potential exploitation of these alterations to improve the treatment of lung cancer patients.
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