ATDC binds to KEAP1 to drive NRF2-mediated tumorigenesis and chemoresistance in pancreatic cancer

Genes Dev. 2021 Feb 1;35(3-4):218-233. doi: 10.1101/gad.344184.120. Epub 2021 Jan 14.


Pancreatic ductal adenocarcinoma is a lethal disease characterized by late diagnosis, propensity for early metastasis and resistance to chemotherapy. Little is known about the mechanisms that drive innate therapeutic resistance in pancreatic cancer. The ataxia-telangiectasia group D-associated gene (ATDC) is overexpressed in pancreatic cancer and promotes tumor growth and metastasis. Our study reveals that increased ATDC levels protect cancer cells from reactive oxygen species (ROS) via stabilization of nuclear factor erythroid 2-related factor 2 (NRF2). Mechanistically, ATDC binds to Kelch-like ECH-associated protein 1 (KEAP1), the principal regulator of NRF2 degradation, and thereby prevents degradation of NRF2 resulting in activation of a NRF2-dependent transcriptional program, reduced intracellular ROS and enhanced chemoresistance. Our findings define a novel role of ATDC in regulating redox balance and chemotherapeutic resistance by modulating NRF2 activity.

Keywords: ATDC (Trim29); chemotherapeutic resistance; pancreatic cancer; tumor growth and invasion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Carcinogenesis / genetics*
  • DNA-Binding Proteins / metabolism*
  • Drug Resistance, Neoplasm / genetics*
  • Humans
  • Kelch-Like ECH-Associated Protein 1 / metabolism*
  • NF-E2-Related Factor 2 / metabolism*
  • Pancreatic Neoplasms / physiopathology*
  • Protein Binding
  • Transcription Factors / metabolism*


  • DNA-Binding Proteins
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • TRIM29 protein, human
  • Transcription Factors

Supplementary concepts

  • Pancreatic Carcinoma