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.
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Acknowledgements
We would like to thank Professor Zhihua Wang for critical reading of the manuscript and Professor Bo Zhong for the Ubiquitin48-HA plasmid. This work was supported by the National Natural Science Foundation of China [31501148, 81470375].
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Zhang, Q., Zhang, ZY., Du, H. et al. DUB3 deubiquitinates and stabilizes NRF2 in chemotherapy resistance of colorectal cancer. Cell Death Differ 26, 2300–2313 (2019). https://doi.org/10.1038/s41418-019-0303-z
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DOI: https://doi.org/10.1038/s41418-019-0303-z
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