Abstract
Chemotherapy resistance is a major problem in non-small cell lung cancer (NSCLC) treatment. A major mechanism of chemoresistance involves stabilization of the NRF2 transcription factor. NRF2 levels are normally tightly regulated through interaction with KEAP1, an adaptor that targets NRF2 to the CUL3 E3 ubiquitin ligase for proteolysis. In NSCLC, aberrant NRF2 stabilization is best understood through mutations in NRF2, KEAP1, or CUL3 that disrupt their interaction. Biochemical studies, however, have revealed that NRF2 can also be stabilized through expression of KEAP1-interacting proteins that competitively sequester KEAP1 away from NRF2. Here, we have identified PIDD, as a novel KEAP1-interactor in NSCLC that regulates NRF2. We show that this interaction allows PIDD to reduce NRF2 ubiquitination and increase its stability. We also demonstrate that PIDD promotes chemoresistance in NSCLC cells both in vitro and in vivo, and that this effect is dependent on NRF2. Finally, we report that NRF2 protein expression in a NSCLC cohort exceeds the typical incidence of combined NRF2, KEAP1, and CUL3 mutations, and that NRF2 expression in this cohort is correlated with PIDD levels. Our data identify PIDD as a new NRF2 regulator, and suggest that variations in PIDD levels contribute to differential chemosensitivities among NSCLC patients.
Highlights
Lung cancer is the leading cause of cancer-related death worldwide, with the majority of patients having non-small cell lung cancer (NSCLC)[1]
When considering the cumulative alteration frequencies of all three genes as an overall assessment of pathway activation, the top two cancers of 31 surveyed malignancies were lung squamous cell carcinoma (35.96%) and lung adenocarcinoma (23.48%), the two main types of NSCLC, which are shown in Supplementary Fig. S1 (Panel A)
Since some Kelch-like ECH-associated protein 1 (KEAP1)-interacting proteins can indirectly regulate NF-E2-related factor 2 (NRF2) levels by sequestering KEAP1and the CUL3-dependent ubiquitylating machinery away from NRF226–28, we investigated whether protein with a death domain (PIDD) could regulate NRF2 ubiquitination
Summary
Lung cancer is the leading cause of cancer-related death worldwide, with the majority of patients having non-small cell lung cancer (NSCLC)[1]. NF-E2-related factor 2 (NRF2) is a transcription factor whose activation in cancer cells has been implicated in resistance to chemotherapy[8] It directly regulates a battery of downstream anti-oxidant genes, including (1) intracellular redox-balancing proteins (glutamate cysteine ligase, GCL; heme oxygenase-1, HO-1), (2) xenobiotic metabolizing enzymes (NAD[P]H quinone oxidoreductase-1, NQO1), and (3) transporters (multidrug resistance-associated proteins, MRPs). These genes function in a vast array of processes to protect www.nature.com/scientificreports/. Www.nature.com/scientificreports against oxidative stress and harmful environmental toxicants and carcinogens Consistent with these molecular functions, high levels of NRF2 in NSCLC are associated with resistance to chemotherapy and poor prognosis[9]. We provide evidence for PIDD being a new clinically relevant regulator of NRF2 and NSCLC malignancy and chemoresistance, and suggest that its further study may yield insight into novel treatment options for NSCLC
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