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ARID2 deficiency promotes tumor progression and is associated with higher sensitivity to chemotherapy in lung cancer

Oncogene volume 40, pages 2923–2935 (2021)Cite this article

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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.

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Fig. 1: Frequent ARID2 mutations associated with protein loss.
Fig. 2: ARID2 deficiency is associated with an increase in oncogenesis in vitro and in vivo.
Fig. 3: Profound chromatin structural changes on enhancers affect gene expression after ARID2 loss.
Fig. 4: ARID2 deficiency affects DNA repair and affects sensitivity to antitumor therapies.

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Data availability

DNA-Seq, ATAC-Seq, and RNA-Seq data: https://www.ebi.ac.uk/ena/data/search?query=PRJEB26936.

Code availability

All computer code is available upon request.

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Acknowledgements

In memoriam of Carlos Revilla, we will miss you forever. We would like to thank the support of the funding agencies Ministerio de Economía y Competitividad, Fundación Ramón Areces, European Research Council, Asociación Española contra el cáncer, Cancer Research UK, UK Medical Research Council, Wellcome Trust, Servicio de Salud del Principado de Asturias, Instituto de Salud Carlos III and Fundación Bancaria Cajastur (specific grant references are included in the funding support section). We will like to thank as well the technical support of the different institutions and common services as well as the patients that agreed to participate in this study. We finally want to thank Dr Francisco Real, Dr Roland Rad, Dr Jose Pedro Vaqué, and Dr Javier Leon for providing critical reagents and advice as well as to all the patients that agreed to participate in this study. For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.

Funding

IV is supported by SAF2012-31627 and SAF2016-76758-R grants from the Spanish Ministerio de Economía y Competitividad (MINECO), by a Fundación Ramón Areces grant and by ERC2014-StG637904 grant from the European Research Council. IV has been awardee of the Programa Ramón y Cajal (MINECO, Spain). TM has been awardee of the Ayudas para la contratación de investigadores predoctorales (MINECO, Spain). BM is awardee of the Ayudas para la formación de profesorado universitario (FPU, Ministerio de Educación y Formación Profesional, Spain). PC laboratory is supported by grant SAF-2015-63638R (MINECO/FEDER, UE); by Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) and by Asociación Española Contra el Cáncer (AECC), grant GCB141423113. BC has been supported by a Retos Jóvenes Investigadores grant SAF-2015-73364-JIN (AEI/FEDER, UE) and a grant from Fundación Francisco Cobos. PS is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001152) and the UK Medical Research Council (FC001152). HUCA/IUOPA is jointly financed by Servicio de Salud del Principado de Asturias, Instituto de Salud Carlos III, and Fundación Bancaria Cajastur. This research was funded in part by the Wellcome Trust [FC001152].

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  1. Deceased: Carlos Revilla

Authors and Affiliations

  1. Instituto de Biomedicina y Biotecnología de Cantabria, Universidad de Cantabria-CSIC, Santander, Spain

    Thaidy Moreno, Beatriz Monterde, Laura González-Silva, Carlos Revilla, Antonio Agraz-Doblas, Laura Quevedo, Rosa Blanco, Berta Casar, Piero Crespo & Ignacio Varela

  2. Departamento de Patología, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Tenerife, Spain

    Isabel Betancor-Fernández & Eduardo Salido

  3. Servicio de Anatomía Patológica y Biobanco Valdecilla, HUMV/IDIVAL, Santander, Spain

    Javier Freire, Santiago Montes-Moreno, Laura Cereceda & Javier Gómez-Román

  4. Biobanco del Principado de Asturias (BBPA), Hospital Universitario Central de Asturias, Oviedo, Spain

    Pablo Isidro & Aurora Astudillo

  5. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain

    Berta Casar & Piero Crespo

  6. Cancer Epigenetics Laboratory, The Francis Crick Institute, London, UK

    Cristina Morales Torres & Paola Scaffidi

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Correspondence to Ignacio Varela.

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Moreno, T., Monterde, B., González-Silva, L. et al. ARID2 deficiency promotes tumor progression and is associated with higher sensitivity to chemotherapy in lung cancer. Oncogene 40, 2923–2935 (2021). https://doi.org/10.1038/s41388-021-01748-y

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