| Literature DB >> 30778200 |
Qi Zhang1, Ze-Yan Zhang2, Huan Du1, Shang-Ze Li3, Rongfu Tu1, Yi-Fan Jia4, Zhe Zheng5, Xue-Min Song6, Run-Lei Du7, Xiao-Dong Zhang8.
Abstract
The transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) is one of the master regulators that control hundreds of genes containing antioxidant response elements (AREs). The NRF2-ARE pathway plays a complex role in colorectal cancer (CRC). NRF2 activity is known to be regulated by KEAP1-CUL3 E3 ligase-mediated ubiquitination, indicating the importance of deubiquitination regulation. However, the deubiquitinase (DUB) of NRF2 remains unknown. Here, by screening a DUB library, we identified DUB3 as a DUB that remarkably stabilized NRF2. Further experiments demonstrated that DUB3 promoted NRF2 stability and transcriptional activity by decreasing the K48-linked ubiquitination of NRF2. Coimmunoprecipitation studies revealed interactions between NRF2 and DUB3, as well as between KEAP1 and DUB3, indicating that NRF2, DUB3, and KEAP1 formed a large functional complex. Importantly, ectopic expression of DUB3 caused NRF2-dependent chemotherapy resistance in colon cancer cell lines. Thus, to the best of our knowledge, our findings are the first to identify DUB3 as a NRF2 DUB and may provide a new strategy against chemotherapy resistance in CRC and other NRF2-related diseases.Entities:
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Year: 2019 PMID： 30778200 PMCID： PMC6889501 DOI： 10.1038/s41418-019-0303-z
Source DB: PubMed Journal: Cell Death Differ ISSN： 1350-9047 Impact factor: 15.828