Gankyrin has an antioxidative role through the feedback regulation of Nrf2 in hepatocellular carcinoma

Yang, Chun; Tan, Ye-Xiong; Yang, Guosheng; Zhang, Jian; Liu, Chen; Fu, Jianzhong; Chen, Yao; Ding, Zhiwen; Liang, Dong; Wang, Hongyang

doi:10.1083/jcb.2132oia86

Cited by 7 publications

(21 citation statements)

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“…104 In this case, PSMD10 competes with NRF2 for Keap1 which subsequently leads to proteasome degradation. Rescue of NRF2 by this mechanism that was discovered in hepatocellular carcinoma cells results in production of new PSMD10 and other proteasome units that are transcriptional targets of NRF2 in a positive feed-forward loop.…”

Section: Rbx1mentioning

confidence: 99%

“…102 Regulation of PSMD10 transcription is activated by β-catenin and c-myc, 103 in addition to the general transcription panel members regulating other proteasome units expression, such as NRF2. 104 PSMD10 is a ubiquitin receptor and is involved in facilitation of degradation of both tumor suppressors p53 and Rb by the proteasome. 105 Moreover, in hepatocellular carcinoma cells, PSMD10 interfered with the interaction of Oct4 with E3 ligase WWP2, impeding the degradation of the pluripotency transcription factor and promoting the expansion of tumor-initiating cells.…”

Section: Rbx1mentioning

confidence: 99%

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Proteasome expression and activity in cancer and cancer stem cells

Voutsadakis

2017

Tumour Biol.

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Proteasome is a multi-protein organelle that participates in cellular proteostasis by destroying damaged or short-lived proteins in an organized manner guided by the ubiquitination signal. By being in a central place in the cellular protein complement homeostasis, proteasome is involved in virtually all cell processes including decisions on cell survival or death, cell cycle, and differentiation. These processes are important also in cancer, and thus, the proteasome is an important regulator of carcinogenesis. Cancers include a variety of cells which, according to the cancer stem cell theory, descend from a small percentage of cancer stem cells, alternatively termed tumor-initiating cells. These cells constitute the subsets that have the ability to propagate the whole variety of cancer and repopulate tumors after cytostatic therapies. Proteasome plays a role in cellular processes in cancer stem cells, but it has been found to have a decreased function in them compared to the rest of cancer cells. This article will discuss the transcriptional regulation of proteasome sub-unit proteins in cancer and in particular cancer stem cells and the relationship of the proteasome with the pluripotency that is the defining characteristic of stem cells. Therapeutic opportunities that present from the understanding of the proteasome role will also be discussed.

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Section: Rbx1mentioning

confidence: 99%

Section: Rbx1mentioning

confidence: 99%

Proteasome expression and activity in cancer and cancer stem cells

Voutsadakis

2017

Tumour Biol.

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“…The KEAP1/NRF2/ARE signaling pathway plays an important role in cellular antioxidant processes . Multiple proteins, such as P21, PALB2 and gankyrin, have been reported to affect the expression of key molecules in the signaling pathway regulating cellular antioxidant processes . We found that RMP enhanced NRF2 protein stability not by affecting the overall ubiquitin proteasome activity, but by stabilizing the NRF2 protein through competitively binding to the Kelch domain in KEAP1, thus increasing cellular antioxidant activity.…”

Section: Discussionmentioning

confidence: 70%

“…Somatic mutations of NRF2 or KEAP1 in their interacting domain that weaken their binding with each other have been detected in multiple cancers . Moreover, some proteins have been reported to compete for binding with NRF2 or KEAP1, disrupting this interaction and subsequent NRF2 activation …”

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confidence: 99%

RPB5‐Mediating Protein Promotes Cholangiocarcinoma Tumorigenesis and Drug Resistance by Competing With NRF2 for KEAP1 Binding

et al. 2020

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BaCKgRoUND aND aIMS:Cancer cell survival depends on the balance between reactive oxygen species production and scavenging, which is regulated primarily by NRF2 during tumorigenesis. Here, we demonstrate that deletion of RBP5mediating protein (RMP) in an autonomous mouse model of intrahepatic cholangiocarcinoma (ICC) delays tumor progression. appRoaCH aND ReSUltS: RMP-overexpressing tumor cells exhibited enhanced tolerance to oxidative stress and apoptosis. Mechanistically, RMP competes with NRF2 for binding to the Kelch domain of KEAP1 (Kelch-like ECH-associated protein 1) through the E**E motif, leading to decreased NRF2 degradation via ubiquitination, thus increasing NRF2 nuclear translocation and downstream transactivation of antioxidant genes. This RMP-KEAP1-NRF2 axis promotes ICC tumorigenesis, metastasis, and drug resistance. Consistent with these findings, the RMP level in human ICC is positively correlated with the protein level of NRF2 and is associated with poor prognosis.CoNClUSIoN: These findings reveal that RMP is involved in the oxidative stress defense program and could be exploited for targeted cancer therapies. (Hepatology 2020;71:2005-2022.

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“…We infer that increased ROS formation, c-myc expression and Akt-MAPK pathway activation may explain how MC-LR mediates increased gankyrin levels. ROS formation has been reported to contribute to gankyrin activation [30,31]. In addition, c-myc, as an oncogene induced by MC-LR, was also demonstrated to be a transcriptional activator of gankyrin [32].…”

Section: Cellular Physiology and Biochemistry Cellular Physiology Andmentioning

confidence: 99%

Chronic Microcystin-LR Exposure Induces Hepatocarcinogenesis via Increased Gankyrin in Vitro and in Vivo

He¹,

Huang²,

Guo³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Our recent study indicated that the serum microcystin-LR (MC-LR) level is positively linked to the risk of human hepatocellular carcinoma (HCC). Gankyrin is over-expressed in cancers and mediates oncogenesis; however, whether MC-LR induces tumor formation and the role of gankyrin in this process is unclear. Methods: We induced malignant transformation of L02 liver cells via 35 passages with exposure to 1, 10, or 100 nM MC-LR. Wound healing, plate and soft agar colony counts, and nude mice tumor formation were used to evaluate the tumorigenic phenotype of MC-LR-treated cells. Silencing gankyrin was used to confirm its function. We established a 35-week MC-LR exposure rat model by twice weekly intraperitoneal injection with 10 μg/kg body weight. In addition, 96 HCC patients were tested for tumor tissue gankyrin expression and serum MC-LR levels. Results: Chronic low-dose MC-LR exposure increased proliferation, mobility, clone and tumor formation abilities of L02 cells as a result of gankyrin activation, while silencing gankyrin inhibited the carcinogenic phenotype of MC-LR-treated cells. MC-LR also induced neoplastic liver lesions in Sprague-Dawley rats due to up-regulated gankyrin. Furthermore, a trend of increased gankyrin was observed in humans exposed to MC-LR. Conclusion: These results suggest that MC-LR induces hepatocarcinogenesis in vitro and in vivo by increasing gankyrin levels, providing new insight into MC-LR carcinogenicity studies.

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Gankyrin has an antioxidative role through the feedback regulation of Nrf2 in hepatocellular carcinoma

Cited by 7 publications

References 50 publications

Proteasome expression and activity in cancer and cancer stem cells

Proteasome expression and activity in cancer and cancer stem cells

RPB5‐Mediating Protein Promotes Cholangiocarcinoma Tumorigenesis and Drug Resistance by Competing With NRF2 for KEAP1 Binding

Chronic Microcystin-LR Exposure Induces Hepatocarcinogenesis via Increased Gankyrin in Vitro and in Vivo

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