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HSP110 translocates to the nucleus upon genotoxic chemotherapy and promotes DNA repair in colorectal cancer cells

Oncogene volume 38, pages 2767–2777 (2019)Cite this article

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Abstract

A multicenter clinical study demonstrated the presence of a loss-of-function HSP110 mutation in about 15% of colorectal cancers, which resulted from an alternative splicing and was produced at the detriment of wild-type HSP110. Patients expressing low levels of wild-type HSP110 had excellent outcomes (i.e. response to an oxaliplatin-based chemotherapy). Here, we show in vitro, in vivo, and in patients’ biopsies that HSP110 co-localizes with DNA damage (γ-H2AX). In colorectal cancer cells, HSP110 translocates into the nucleus upon treatment with genotoxic chemotherapy such as oxaliplatin. Furthermore, we show that HSP110 interacts with the Ku70/Ku80 heterodimer, an essential element of the non-homologous end joining (NHEJ) repair machinery. We also demonstrate by evaluating the resolved 53BP1 foci that depletion in HSP110 impairs repair steps of the NHEJ pathway, which is associated with an increase in DNA double-strand breaks and in the cells’ sensitivity to oxaliplatin. HSP110-depleted cells sensitization to oxaliplatin-induced DNA damage is abolished upon re-expression of HSP110. Confirming a role for HSP110 in DNA non-homologous repair, SCR7 and NU7026, two inhibitors of the NHEJ pathway, circumvents HSP110-induced resistance to chemotherapy. In conclusion, HSP110 through its interaction with the Ku70/80 heterodimer may participate in DNA repair, thereby inducing a protection against genotoxic therapy.

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Acknowledgements

We are grateful professor Gorbunova for allowing us using her NHEJ DNA repair system and to Alex Duval and Ada Collura for helpful discussions. We also thank the Platforms of cytometry Cellimap. This work was supported by grants from the Institut National du Cancer, Ligue Nationale Contre le Cancer, and the Conseil Régional de Bourgogne. The work was also supported by a French Government grant managed by the French National Research Agency under the program “Investissements d’Avenir” with reference ANR-11-LABX-0021 (LabEX LipSTIC). We thank the European Union programme FEDER for their financial support. SC had a fellowship from La Ligue Nationale contre le Cancer, GM from the Association pour la Recherche sur le Cancer, GG from the «Fondation de France», and GC from the «Fondation pour la Recherche Médicale (ECO20160736090)».

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Authors and Affiliations

  1. INSERM UMR 1231, «Equipe labellisée» Ligue National contre le Cancer and Laboratoire d’Excellence LipSTIC, Dijon, France

    Sebastien Z. Causse, Guillaume Marcion, Gaëtan Chanteloup, Burhan Uyanik, Christophe Boudesco, Bogdan B. Grigorash, Romain Douhard, Alexandre M. M. Dias, Baptiste Dumetier, Lucile Dondaine, Gustavo J. Gozzi, Laurence Dubrez, Oleg N. Demidov, Jessica Gobbo & Carmen Garrido

  2. Université de Bourgogne-Franche Comté, Dijon, France

    Sebastien Z. Causse, Guillaume Marcion, Gaëtan Chanteloup, Burhan Uyanik, Christophe Boudesco, Bogdan B. Grigorash, Romain Douhard, Alexandre M. M. Dias, Baptiste Dumetier, Lucile Dondaine, Gustavo J. Gozzi, Laurence Dubrez, Oleg N. Demidov, Jessica Gobbo & Carmen Garrido

  3. Luxembourg Institute of Health, 84, Val Fleuri, L-1526, Luxembourg, Luxembourg

    Etienne Moussay & Jérôme Paggetti

  4. Anticancer Center Georges François Leclerc-Unicancer, Dijon Cedex, France

    Céline Mirjolet, Jessica Gobbo & Carmen Garrido

  5. Unité « Epigénétique et Destin cellulaire», Université Paris Diderot, Paris, France

    Aurélie de Thonel

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  1. Sebastien Z. Causse
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  2. Guillaume Marcion
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  19. Carmen Garrido
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Correspondence to Carmen Garrido.

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Causse, S.Z., Marcion, G., Chanteloup, G. et al. HSP110 translocates to the nucleus upon genotoxic chemotherapy and promotes DNA repair in colorectal cancer cells. Oncogene 38, 2767–2777 (2019). https://doi.org/10.1038/s41388-018-0616-2

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