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Sensitization of retinoids and corticoids to epigenetic drugs in MYC-activated lung cancers by antitumor reprogramming

Oncogene volume 36, pages 1287–1296 (2017)Cite this article

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Abstract

Components of the SWI/SNF chromatin remodeling complex, including BRG1 (also SMARCA4), are inactivated in cancer. Among other functions, SWI/SNF orchestrates the response to retinoid acid (RA) and glucocorticoids (GC) involving downregulation of MYC. The epigenetic drugs SAHA and azacytidine, as well as RA and GC, are currently being used to treat some malignancies but their therapeutic potential in lung cancer is not well established. Here we aimed to determine the possible therapeutic effects of azacytidine and SAHA (A/S) alone or in combination with GC plus RA (GC/RA) in lung cancers with either BRG1 inactivation or MYC amplification. In vitro, responses to GC/RA treatment were more effective in MYC-amplified cells. These effects were mediated by BRG1 and involved a reprogramming towards prodifferentiation gene expression signatures and downregulation of MYC. In MYC-amplified cells, administration of GC/RA enhanced the cell growth inhibitory effects of A/S which, in turn, accentuated the prodifferentiation features promoted by GC/RA. Finally, these treatments improved overall survival of mice orthotopically implanted with MYC-amplified, but not BRG1-mutant, cells and reduced tumor cell viability and proliferation. We propose that the combination of epigenetic treatments with retinoids and corticoids of MYC-driven lung tumors constitute a strategy for therapeutic intervention in this otherwise incurable disease.

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Acknowledgements

We thank Patricia Cabral (Genes and Cancer Group) at IDIBELL for technical assistance. This work was supported by the grants from the Spanish MINECO SAF2011-22897, Institute of Health Carlos III (ISCIII)-PIE13/00022 (ONCOPROFILE) and RTICC (RD12/0036/0045 to MS-C and RD12/0036/0039 to ME) and a grant from the Fundación Científica Asociacion Española Contra el Cáncer-GCB14-2170. MT-D is supported by a fellowship from the Spanish MINECO. Funding was also provided by the European Union Seventh Framework Programme (FP7/2007-13), under grant agreement HEALTH-F2-2010-258677–CURELUNG.

Author contributions

OAR, MT-D and SV performed and analyzed most of the experiments. SM performed the DNA methylation microarrays. AG and SM analyzed the bioinformatic data. SV and EC performed and analyzed the histopathological work. AV generated the mouse models and designed/supervised the mouse work. ME supervised the global DNA methylation analysis. OAR and MS-C designed the overall study. MS-C supervised the research and wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Author notes

  1. O A Romero and S Verdura: These authors contributed equally to this work.

Authors and Affiliations

  1. Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute-IDIBELL, Barcelona, Spain

    O A Romero, S Verdura, M Torres-Diz & M Sanchez-Cespedes

  2. Cancer Epigenetics Groups, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute-IDIBELL, Barcelona, Spain

    A Gomez, S Moran & M Esteller

  3. Pathology Department, Bellvitge Hospital, Barcelona, Spain

    E Condom

  4. Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute-IDIBELL, Barcelona, Spain

    A Villanueva

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  1. O A Romero
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Correspondence to M Sanchez-Cespedes.

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Romero, O., Verdura, S., Torres-Diz, M. et al. Sensitization of retinoids and corticoids to epigenetic drugs in MYC-activated lung cancers by antitumor reprogramming. Oncogene 36, 1287–1296 (2017). https://doi.org/10.1038/onc.2016.296

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