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AATF suppresses apoptosis, promotes proliferation and is critical for Kras-driven lung cancer

Oncogene volume 37, pages 1503–1518 (2018)Cite this article

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Abstract

A fundamental principle in malignant tranformation is the ability of cancer cells to escape the naturally occurring cell-intrinsic responses to DNA damage. Tumors progress despite the accumulation of DNA lesions. However, the underlying mechanisms of this tolerance to genotoxic stress are still poorly characterized. Here, we show that replication stress occurs in Kras-driven murine lung adenocarcinomas, as well as in proliferating murine embryonic and adult tissues. We identify the transcriptional regulator AATF/CHE-1 as a key molecule to sustain proliferative tissues and tumor progression in parts by inhibiting p53-driven apoptosis in vivo. In an autochthonous Kras-driven lung adenocarcinoma model, deletion of Aatf delayed lung cancer formation predominantly in a p53-dependent manner. Moreover, targeting Aatf in existing tumors through a dual recombinase strategy caused a halt in tumor progression. Taken together, these data suggest that AATF may serve as a drug target to treat KRAS-driven malignancies.

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Acknowledgements

The authors thank Alexandra Florin, Marion Müller and Ursula Rommerscheidt-Fuß, Institute of Pathology and Martyna Brütting, CECAD, University Hospital Cologne, for their outstanding technical support.

Funding

This work was supported by Volkswagenstiftung (Lichtenberg Program to HCR), Deutsche Forschungsgemeinschaft (KFO-286 to HCR, SFB-829 to HCR, CN and TB, SCHE1562/2 to BS, BE2212 to TB), Bundesministerium für Bildung und Forschung (SMOOSE to HCR, SYBACOL to TB), German federal state North Rhine Westphalia (NRW) as part of the EFRE initiative (grant LS-1-1-030a to HCR), Else Kröner-Fresenius Stiftung (EKFS-2014-A06 to HCR), Deutsche Krebshilfe (111724, HCR), University of Cologne (Köln Fortune Program to KH), Cologne Cardiovascular Research Center (Graduate Program to MJ), Cologne Graduate School of Ageing Research (to SK), CECAD Research Center Cologne Maternity Leave Fellowship to DW.

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Author notes

  1. Daniela Welcker, Manaswita Jain and Safiya Khurshid contributed equally to this work.

Authors and Affiliations

  1. Department II of Internal Medicine, University of Cologne, Cologne, Germany

    Daniela Welcker, Manaswita Jain, Safiya Khurshid, Martin Höhne, Anna Schmitt, Bernhard Schermer, Thomas Benzing & Katja Höpker

  2. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

    Daniela Welcker, Manaswita Jain, Safiya Khurshid, Mladen Jokić, Martin Höhne, Peter Frommolt, Carien M. Niessen, Bernhard Schermer, Hans Christian Reinhardt, Thomas Benzing & Katja Höpker

  3. Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA

    Safiya Khurshid

  4. Department I of Internal Medicine, University of Cologne, Cologne, Germany

    Mladen Jokić & Hans Christian Reinhardt

  5. Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany

    Mladen Jokić, Martin Höhne, Carien M. Niessen, Bernhard Schermer, Hans Christian Reinhardt & Thomas Benzing

  6. Systems Biology of Ageing Cologne (Sybacol), University of Cologne, Cologne, Germany

    Martin Höhne, Bernhard Schermer & Thomas Benzing

  7. Department of Dermatology, University of Cologne, Cologne, Germany

    Carien M. Niessen

  8. Department of Radiology, University of Cologne, Cologne, Germany

    Judith Spiro & Thorsten Persigehl

  9. Department of Pathology, University of Cologne, Cologne, Germany

    Maike Wittersheim & Reinhard Büttner

  10. Department of Research, Advanced Diagnostics and Technological Innovation, SAFU Laboratory, Translational Research Area, Regina Elena National Cancer Institute, Rome, Italy

    Maurizio Fanciulli

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  1. Daniela Welcker
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  2. Manaswita Jain
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Correspondence to Hans Christian Reinhardt or Thomas Benzing.

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HCR received consulting fees from Abbvie, Vertex, AstraZeneca and Merck. HCR received research funding from Gilead. All other authors declare that they have no competing interests.

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Welcker, D., Jain, M., Khurshid, S. et al. AATF suppresses apoptosis, promotes proliferation and is critical for Kras-driven lung cancer. Oncogene 37, 1503–1518 (2018). https://doi.org/10.1038/s41388-017-0054-6

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