Research ArticleCancer

GULP1 regulates the NRF2-KEAP1 signaling axis in urothelial carcinoma

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Science Signaling  18 Aug 2020:
Vol. 13, Issue 645, eaba0443
DOI: 10.1126/scisignal.aba0443

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Suppressing an NRF2 inhibitor in cancer

Because of high metabolic activity, cancer cells often experience greater oxidative load compared to normal cells. Many types of cancer increase antioxidant signaling mediated by the transcription factor NRF2 to survive oxidative stress. Hayashi et al. found that deficiency of the phagocytic adaptor protein GULP1 increased the nuclear localization and, therefore, activity of NRF2 in urothelial carcinoma of the bladder (UCB). Cisplatin-resistant cell lines and aggressive UCB patient samples had decreased GULP1 abundance. GULP1 expression was inversely correlated with promoter hypermethylation, which could be detected in the urine of some patients with UCB. These results highlight a possible biomarker and therapeutic target for UCB, which imposes a high lifetime financial burden on patients.


Disruption of the KEAP1-NRF2 pathway results in the transactivation of NRF2 target genes, consequently inducing cell proliferation and other phenotypic changes in cancer cells. Here, we demonstrated that GULP1 was a KEAP1-binding protein that maintained actin cytoskeleton architecture and helped KEAP1 to sequester NRF2 in the cytoplasm. In urothelial carcinoma of the bladder (UCB), silencing of GULP1 facilitated the nuclear accumulation of NRF2, led to constitutive activation of NRF2 signaling, and conferred resistance to the platinum drug cisplatin. Knockdown of GULP1 in UCB cells promoted tumor cell proliferation in vitro and enhanced tumor growth in vivo. In primary UCB, GULP1 silencing was more prevalent in muscle-invasive UCB compared to nonmuscle-invasive UCB. GULP1 knockdown cells showed resistance to cisplatin treatment. In parallel with decreased GULP1 expression, we observed increased expression of NRF2, HMOX1, and other candidate antioxidant genes in cisplatin-resistant cells. Furthermore, low or no expression of GULP1 was observed in most cisplatin nonresponder cases. Silencing of GULP1 was associated with GULP1 promoter hypermethylation in cell lines and primary tumors, and a high frequency of GULP1 promoter methylation was observed in multiple sets of primary clinical UCB samples. Together, our findings demonstrate that GULP1 is a KEAP1-binding protein that regulates KEAP1-NRF2 signaling in UCB and that promoter hypermethylation of GULP1 is a potential mechanism of GULP1 silencing.

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