title: Epigenetic Regulation of KPC1 Ubiquitin Ligase Affects the NF-κB Pathway in Melanoma.
abstract: Purpose:Abnormal activation of the NF-κB pathway induces a more aggressive phenotype of cutaneous melanoma. Understanding the mechanisms involved in melanoma NF-κB activation may identify novel targets for this pathway. KPC1, an E3 ubiquitin ligase, is a regulator of the NF-κB pathway. The objective of this study was to investigate the mechanisms regulating KPC1 expression and its clinical impact in melanoma.Experimental Design:The clinical impact of KPC1 expression and its epigenetic regulation were assessed in large cohorts of clinically well-annotated melanoma tissues (tissue microarrays;n= 137, JWCI cohort;n= 40) and The Cancer Genome Atlas database (TCGA cohort,n= 370). Using melanoma cell lines, we investigated the functional interactions between KPC1 and NF-κB, and the epigenetic regulations of KPC1, including DNA methylation and miRNA expression.Results:We verified that KPC1 suppresses melanoma proliferation by processing NF-κB1 p105 into p50, thereby modulating NF-κB target gene expression. Concordantly, KPC1 expression was downregulated in American Joint Committee on Cancer stage IV melanoma compared with early stages (stage I/IIP= 0.013, stage IIIP= 0.004), and low KPC1 expression was significantly associated with poor overall survival in stage IV melanoma (n= 137; HR 1.810;P= 0.006). Furthermore, our data showed that high miR-155-5p expression, which is controlled by DNA methylation at its promoter region (TCGA; Pearson'sr-0.455;P< 0.001), is significantly associated with KPC1 downregulation (JWCI;P= 0.028, TCGA;P= 0.003).Conclusions:This study revealed novel epigenetic regulation of KPC1 associated with NF-κB pathway activation, promoting metastatic melanoma progression. These findings suggest the potential utility of KPC1 and its epigenetic regulation as theranostic targets.Clin Cancer Res; 23(16); 4831-42. ©2017 AACR.
authors.affiliation: Division of Molecular Oncology, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Iida
authors.affiliation: The David and Janet Polak Cancer and Vascular Biology Research Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Bat-Galim, Haifa, Israel.
authors.forename: Aaron
authors.initials: A
authors.lastname: Ciechanover
authors.affiliation: Division of Molecular Oncology, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California.
authors.forename: Diego M
authors.initials: DM
authors.lastname: Marzese
authors.affiliation: Division of Molecular Oncology, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hata
authors.affiliation: Division of Molecular Oncology, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California.
authors.forename: Matias
authors.initials: M
authors.lastname: Bustos
authors.affiliation: Division of Molecular Oncology, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California.
authors.forename: Shigeshi
authors.initials: S
authors.lastname: Ono
authors.affiliation: Division of Molecular Oncology, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Division of Molecular Oncology, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Salomon
authors.affiliation: Division of Molecular Oncology, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California.
authors.forename: Kevin
authors.initials: K
authors.lastname: Tran
authors.affiliation: Division of Molecular Oncology, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California.
authors.forename: Stella
authors.initials: S
authors.lastname: Lam
authors.affiliation: John Wayne Cancer Institute Genome Sequencing Center, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California.
authors.forename: Sandy
authors.initials: S
authors.lastname: Hsu
authors.affiliation: John Wayne Cancer Institute Genome Sequencing Center, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California.
authors.forename: Nellie
authors.initials: N
authors.lastname: Nelson
authors.affiliation: The David and Janet Polak Cancer and Vascular Biology Research Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Bat-Galim, Haifa, Israel.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Kravtsova-Ivantsiv
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.affiliation: Division of Molecular Oncology, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California. hoond@jwci.org.|John Wayne Cancer Institute Genome Sequencing Center, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California.
authors.forename: Dave S B
authors.initials: DSB
authors.lastname: Hoon
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015331:Cohort Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; C574376:RNF123 protein, human; D044767:Ubiquitin-Protein Ligases