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

Daniela Welcker1,2, Manaswita Jain1,2, Safiya Khurshid1,2,3

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

Oncogene
|January 12, 2018
PubMed

Insights

Cancer cells evade DNA damage responses for tumor growth. Researchers found that AATF (che-1) sustains proliferative tissues and tumor progression by inhibiting p53-driven apoptosis, suggesting AATF as a potential drug target for KRAS-driven cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Malignant transformation involves cancer cells evading intrinsic DNA damage responses, allowing tumor progression despite accumulated DNA lesions.
  • Mechanisms underlying cancer cell tolerance to genotoxic stress remain poorly understood.
  • Replication stress is observed in Kras-driven lung adenocarcinomas and other proliferating tissues.

Purpose of the Study:

  • To investigate the mechanisms of DNA damage tolerance in cancer.
  • To identify key molecules involved in sustaining proliferative tissues and tumor progression.
  • To evaluate the therapeutic potential of targeting specific regulators in KRAS-driven malignancies.

Main Methods:

  • Analysis of replication stress in Kras-driven murine lung adenocarcinomas and proliferating tissues.
  • Identification and functional characterization of the transcriptional regulator AATF/CHE-1.
  • In vivo studies involving Aatf deletion in an autochthonous Kras-driven lung adenocarcinoma model.
  • In vivo tumor targeting of Aatf using a dual recombinase strategy.

Main Results:

  • Replication stress is a feature of Kras-driven lung adenocarcinomas and proliferating normal tissues.
  • The transcriptional regulator AATF/CHE-1 was identified as crucial for sustaining proliferative tissues and tumor progression.
  • AATF inhibits p53-driven apoptosis in vivo.
  • Aatf deletion in a Kras-driven lung cancer model delayed tumor formation in a p53-dependent manner.
  • Targeting Aatf in established tumors halted tumor progression.

Conclusions:

  • AATF/CHE-1 plays a critical role in enabling cancer cells to tolerate DNA damage and promote tumor progression.
  • AATF's inhibition of p53-driven apoptosis is key to its function in cancer.
  • AATF represents a potential therapeutic target for KRAS-driven malignancies.

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