Cell Line, Tumor; Cell Proliferation; Cohort Studies; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Kaplan-Meier Estimate; Melanoma; MicroRNAs; NF-kappa B; Promoter Regions, Genetic; RNA Interference; Signal Transduction; Ubiquitin-Protein Ligases
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/II P = 0.013, stage III P = 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's r -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.
Iida, Yuuki; Ciechanover, Aaron; Marzese, Diego M; Hata, Keisuke; Bustos, Matias; Ono, Shigeshi; Wang, Jinhua; Salomon, Matthew P; Tran, Kevin; Lam, Stella; Hsu, Sandy; Nelson, Nellie; Kravtsova-Ivantsiv, Yelena; Mills, Gordon B; Davies, Michael A; and Hoon, Dave S B, "Epigenetic Regulation of KPC1 Ubiquitin Ligase Affects the NF-κB Pathway in Melanoma." (2017). Journal Articles and Abstracts. 441.