Editors' ChoiceCancer

ATDC KEAPs NRF2 active

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Science Signaling  09 Feb 2021:
Vol. 14, Issue 669, eabg9105
DOI: 10.1126/scisignal.abg9105

ATDC promotes pancreatic cancer progression and chemoresistance by disrupting KEAP1-mediated ubiquitylation of NRF2.

Oxidative stress stabilizes NRF2, a key transcriptional activator of cellular antioxidant responses, by causing it to be released from the ubiquitin ligase substrate adaptor KEAP1. To survive the oxidative stress resulting from high metabolic activity, many cancer cells evolve mechanisms to constitutively activate NRF2. Purohit et al. found that ATDC (ataxia-telangiectasia group D–associated gene), which is abundant in pancreatic cancers, directly interacted with KEAP1 in cells and protected NRF2 from proteasome-mediated degradation by disrupting the KEAP1-NRF2 interaction. Knocking down ATDC in patient-derived pancreatic ductal adenocarcinoma (PDAC) cell lines reduced proliferation and invasiveness and increased ROS in a NRF2-dependent manner. Whereas overexpression of wild-type ATDC increased proliferation, invasion, and NRF2 abundance in PDAC cell lines, overexpressing a truncated form of ATDC that was unable to bind to KEAP1 did not. In mice, orthotopic transplantation experiments using PDAC cells expressing various combinations of wild-type ATDC, truncated ATDC, NRF2, and shRNAs targeting ATDC or NRF2 confirmed that ATDC promoted tumor growth and metastasis in a NRF2-dependent manner. Both in vitro and in vivo, the resistance of ATDC-expressing PDAC cells and tumors to the ROS-inducing chemotherapeutic drug gemcitabine depended on NRF2. ATDC abundance in PDAC samples correlated negatively with patient survival. Together, these results suggest that ATDC-mediated disruption of KEAP1-dependent NRF2 degradation contributes to the aggressiveness of PDAC and the propensity of PDAC to readily develop resistance to chemotherapies like gemcitabine.

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