Skp2-mediated Zeb1 expression facilitates cancer migration by a ubiquitination-independent pathway

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Title:	Skp2-mediated Zeb1 expression facilitates cancer migration by a ubiquitination-independent pathway
Authors:	Wang, Hui-Ching Luo, Chi-Wen Chen, Tzu-Yi Chen, Yi-Zi Fang, Shao-Yu Lai, Chiao-Ying Hung, Wen-Chun Wu, Chun-Chieh Chen, Li-Tzong Liu, Yi-Chang Pan, Mei-Ren
Contributors:	Kaohsiung Medical University Kaohsiung Medical University Kaohsiung Medical University Hospital Kaohsiung Medical University Kaohsiung Medical University Hospital Chia Nan University of Pharmacy & Science Chia Nan University of Pharmacy & Science National Health Research Institutes - Taiwan Kaohsiung Medical University Kaohsiung Medical University Hospital Kaohsiung Medical University Kaohsiung Medical University Hospital Kaohsiung Medical University Kaohsiung Medical University Kaohsiung Medical University Hospital
Keywords:	pancreatic ductal adenocarcinoma kinase-associated protein-2 mesenchymal transition skp2 expression drug-resistance cell-growth metastasis inactivation degradation invasion
Date:	2022
Issue Date:	2023-12-11 14:02:07 (UTC+8)
Publisher:	PERGAMON-ELSEVIER SCIENCE LTD
Abstract:	Aims: Pancreatic ductal adenocarcinoma (PDAC) constitutes one of the most dismal malignancies worldwide. Despite multidisciplinary involvement in interventions involving surgery, radiotherapy, and chemotherapy, most pancreatic cancer patients eventually develop distant metastasis. S-phase kinase-associated protein 2 (Skp2) plays an important role in cell-cycle regulation in pancreatic cancer. However, the role of Skp2 in individualized PDAC treatment is largely unknown.Main methods: Immunoblotting, quantitative reverse transcription polymerase chain reaction, cell viability test, chromatin immunoprecipitation assay, and xenograft in vivo assay were performed in parental and Skp2-depleted cells. The immunohistochemistry of Skp2 was analyzed on the tissue microarrays of 45 PDAC cases and mice tissues.Key findings: In this study, we observed that Skp2 is a marker for poor prognosis in PDAC patients. Upregulation of the inhibitor of Kappa B (I Kappa B)-inducing kinase-nuclear factor kappa B (NF-Kappa B) signal cascade mediated Skp2 expression thereby promoting epithelial-mesenchymal transition (EMT). Depletion of NF-Kappa B-associated signaling effectively prevented Skp2-mediated pancreatic cancer cell migration. As a functional consequence, Skp2 orchestrated with Myc to induce zinc finger E-box binding homeobox 1 (Zeb1) transcription by recruiting p300 to the Zeb1 promoter independent of Skp2 E3-ligase activity. Therefore, blockade of Skp2 could significantly reduce the expression of Zeb1 and inhibit cancer cell migration. In conclusion, Skp2 regulated Zeb1 activity to control the migration and invasion abilities of pancreatic cancer cells. Skp2 expression in PDAC may affect cell vulnerability to standard chemotherapy regimens.Significance: Therefore, in patients with PDAC, modulation of Skp2 expression could be a novel strategy for preventing cancer cell metastasis.
Relation:	LIFE SCIENCES, v.311, n.CB2, pp.CC2, pp.-,
Appears in Collections:	[Offices] 123

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