Dataset Information

GSK-3? phosphorylation-dependent degradation of ZNF281 by ?-TrCP2 suppresses colorectal cancer progression.

ABSTRACT: Zinc finger protein 281 (ZNF281) has been recently shown to be critical for CRC progression. However, the immediate upstream regulators of ZNF281 remain unclear. Here we reported that the E3 ligase the ?-transducin repeat-containing protein 2 (?-TrCP2) governs the ubiquitination and degradation of ZNF281. In human CRC specimens, endogenous ?-TrCP2 were inversely correlated with ZNF281. Beta-TrCP2 reversed the phenotype of CRC cell with overexpressed ZNF281. Moreover, we found that glycogen synthase kinase 3? (GSK-3?), not GSK-?, could bind to and phosphorylate ZNF281 at one consensus motif (TSGEHS; phosphorylation site is shown in italics), which promotes the interaction of ZNF281 with ?-TrCP2, not ?-TrCP1, and leads to the subsequent ubiquitination and degradation of phosphorylated ZNF281. A mutant of ZNF281 (ZNF281-S638A) is much more stable than wild-type ZNF281 because ZNF281-S638A mutant abolishes the phosphorylation by GSK-3? and can not be ubiquitinated and degraded by ?-TrCP2. Conversely, ZNF281 transcriptionally repressed the expression of ?-TrCP2, indicating a negative feedback loop between ZNF281 and ?-TrCP2 in CRC cells. These findings suggest that the turnover of ZNF281 by ?-TrCP2 might provide a potentially novel treatment for patients with CRC.

SUBMITTER: Zhu Y

PROVIDER: S-EPMC5687630 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

GSK-3β phosphorylation-dependent degradation of ZNF281 by β-TrCP2 suppresses colorectal cancer progression.

Zhu Yuekun Y Zhou Qingxin Q Zhu Guiling G Xing Yanwei Y Li Shiqiang S Ren Niansheng N Liu Tianyou T Zhu Anlong A Bai Yuxian Y Piao Daxun D

Oncotarget 20170809 51

Zinc finger protein 281 (ZNF281) has been recently shown to be critical for CRC progression. However, the immediate upstream regulators of ZNF281 remain unclear. Here we reported that the E3 ligase the β-transducin repeat-containing protein 2 (β-TrCP2) governs the ubiquitination and degradation of ZNF281. In human CRC specimens, endogenous β-TrCP2 were inversely correlated with ZNF281. Beta-TrCP2 reversed the phenotype of CRC cell with overexpressed ZNF281. Moreover, we found that glycogen synth ...[more]

PMID: 29179460

Similar Datasets

Project description:BackgroundHepatocellular carcinoma (HCC) is the third cause of cancer death in the world, and few molecularly targeted anticancer therapies have been developed to treat it. The E3 ubiquitin ligase RNF152 has been reported to regulate the activity of the mechanistic target of rapamycin complex 1 (mTORC1), induce autophagy and apoptosis. However, the relationship between RNF152 and HCC is unclear.MethodsTranscriptome RNA-sequencing data of HCC samples and normal tissues were used to detect the mRNA expression of RNF152. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to determine the transcriptional regulation of RNF152 in HCC by FoxO1. RNAi, cell proliferation, colony formation and transwell assays were used to determine the in vitro functions of RNF152. Mouse xenograft models were used to study the in vivo effects of RNF152. The immunoprecipitation assay was used to determine the interaction between RNF152 and TSPAN12. The in vivo ubiquitination assay was performed to determine the regulation of TSPAN12 by RNF152.ResultsWe found that RNF152 is significantly down-regulated in clinic HCC samples, and its down-regulation is associated with pool overall survival (OS), progression-free survival (PFS) and disease-specific survival (DSS) in HCC patients. The transcription factor FoxO1 was significantly positively correlated RNF152 expression in HCC tissues. FoxO1 recognizes a classic insulin response element (IRE) on the RNF152 promoter to regulate its expression in HCC. RNF152 suppressed HCC cell proliferation, clonogenic survival, invasion in vitro, and tumorigenesis in vivo. Mechanistically, RNF152 interacted with TSPAN12 and targeted it for ubiquitination and proteasomal degradation, thereby inhibiting TSPAN12-dependent CXCL6 expression and HCC progression.ConclusionCollectively, our data revealed a tumor suppressor role of RNF152 and a connection between RNF152 and FoxO1 in HCC. Our results support an important role of the FoxO1-RNF152-TSPAN12 axis in the development of HCC. Therapeutic targeting this axis may be an effective means of treating HCC.

Dataset Information

GSK-3? phosphorylation-dependent degradation of ZNF281 by ?-TrCP2 suppresses colorectal cancer progression.

Publications

GSK-3β phosphorylation-dependent degradation of ZNF281 by β-TrCP2 suppresses colorectal cancer progression.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure