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HSP110 promotes colorectal cancer growth through STAT3 activation

Oncogene volume 36, pages 2328–2336 (2017)Cite this article

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Abstract

Heat shock protein 110 (HSP110) is induced by different stresses and, through its anti-apoptotic and chaperoning properties, helps cells survive these adverse situations. In colon cancers, HSP110 is abnormally abundant. We have recently shown that colorectal cancer patients with microsatellite instability (MSI) had an improved response to chemotherapy because they harbor an HSP110-inactivating mutation (HSP110DE9). In this work, we used patient biopsies, human colorectal cancer cells grown in vitro and in vivo (xenografts), and intestinal crypts to demonstrate that HSP110 is also involved in colon cancer growth. We showed that HSP110 induces colon cancer cell proliferation and that this effect is associated with STAT3 activation, specifically an increase in STAT3 phosphorylation, nuclear translocation and transcription factor activity. STAT3 inhibition blocks the proliferative effect of HSP110. From a molecular standpoint, we demonstrated that HSP110 directly binds to STAT3, thereby facilitating its phosphorylation by JAK2. Finally, we showed a correlation between HSP110 expression and STAT3 phosphorylation in colon cancer patient samples. Thus, the expression of HSP110 in colon cancer contributes to STAT3–dependent tumor growth and the frequent inactivating mutation of this chaperone is probably an important event underlying the improved prognosis in colon cancer displaying MSI.

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Acknowledgements

This work was supported by grants from the Institut National du Cancer, Agence Nationale de la Recherche, Ligue Nationale Contre le Cancer (‘Labeled teams’ to CG and AD), the Association pour la Recherche sur le Cancer (ARC), the Conseil Regional de Bourgogne, the program ‘Investissements d'Avenir’ ANR-11-LABX-0021-01-LipSTIC LabEx. We thank the FEDER for their support. KB and SC have a doctoral fellowship from La Ligue Nationale Contre le Cancer and KB from La Foundation pour la Recherche Médicale. We thank Prof. Dr Ibrahim M. Adham, Institut für Humangenetik, University of Göttingen for kindly providing the HSP110 KO mice and P Bastable (CHU, Dijon) for the English correction of the manuscript.

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Author notes

  1. K Berthenet, A'dem Bokhari, A Collura, G Jego and C Garrido: These authors contributed equally to this work.

Authors and Affiliations

  1. INSERM, UMR866, Université de Bourgogne Franche-Comté, Faculté des Sciences de Santé, Dijon, France

    K Berthenet, G Marcion, C Boudesco, S Causse, A R Goloudina, A Hammann, O N Demidov, R Seigneuric, G Jego & C Garrido

  2. INSERM, LNC UMR866, Equipe Labellisée Ligue Nationale Contre le Cancer, Dijon, France

    K Berthenet, G Marcion, C Boudesco, S Causse, A R Goloudina, A Hammann, O N Demidov, R Seigneuric, G Jego & C Garrido

  3. INSERM, UMR 938, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Paris, France

    A'dem Bokhari, A Lagrange, M Svrcek, A Duval & A Collura

  4. Université Pierre et Marie Curie-Paris 6, Paris, France

    A'dem Bokhari, A Lagrange, M Svrcek, A Duval & A Collura

  5. CNRS, UMR7216 Epigenetics and Cell Fate, Paris, France

    A De Thonel

  6. AP-HP, Hôpital St Antoine; Service d'Anatomie Pathologique, Paris, France

    S Dumont

  7. Centre d’Etude Atomique, Paris, France

    D S Biard

  8. CGFL, Dijon, France

    C Garrido

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  1. K Berthenet
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  2. A'dem Bokhari
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  3. A Lagrange
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  7. A De Thonel
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  8. M Svrcek
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  9. A R Goloudina
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  10. S Dumont
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  11. A Hammann
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  12. D S Biard
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  14. R Seigneuric
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  15. A Duval
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  16. A Collura
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Corresponding authors

Correspondence to G Jego or C Garrido.

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Berthenet, K., Bokhari, A., Lagrange, A. et al. HSP110 promotes colorectal cancer growth through STAT3 activation. Oncogene 36, 2328–2336 (2017). https://doi.org/10.1038/onc.2016.403

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