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

Daniela Welcker, Manaswita Jain, Safiya Khurshid, Mladen Jokić, Martin Höhne, Anna Schmitt, Peter Frommolt, Carien M. Niessen, Judith Spiro, Thorsten Persigehl, Maike Wittersheim, Reinhard Büttner, Maurizio Fanciulli, Bernhard Schermer, Hans Christian Reinhardt, Thomas Benzing, Katja Höpker

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1-16
Number of pages16
JournalOncogene
DOIs
Publication statusAccepted/In press - Jan 11 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Welcker, D., Jain, M., Khurshid, S., Jokić, M., Höhne, M., Schmitt, A., Frommolt, P., Niessen, C. M., Spiro, J., Persigehl, T., Wittersheim, M., Büttner, R., Fanciulli, M., Schermer, B., Reinhardt, H. C., Benzing, T., & Höpker, K. (Accepted/In press). AATF suppresses apoptosis, promotes proliferation and is critical for Kras-driven lung cancer. Oncogene, 1-16. https://doi.org/10.1038/s41388-017-0054-6