Epigenetic Regulation of KPC1 Ubiquitin Ligase Effects the NF-{kappa}B Pathway in Melanoma

Purpose: Abnormal activation of the NF-B pathway induces a more aggressive phenotype of cutaneous melanoma. Understanding the mechanisms involved in melanoma NF-B activation may identify novel targets for this pathway. KPC1, an E3 ubiquitin ligase, is a regulator of NF-B 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 micro-arrays; 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-B, and the epigenetic regulations of KPC1, including DNA methylation and microRNA expression. Results: We verified that KPC1 suppresses melanoma proliferation by processing NF-B1 p105 into p50, thereby modulating NF-B-target gene expression. Concordantly, KPC1 expression was down-regulated in AJCC stage IV melanoma compared to 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, Hazard Ratio 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 down-regulation (JWCI; p=0.028, TCGA; p=0.003). Conclusions: This study revealed novel epigenetic regulation of KPC1 associated with NF-B pathway activation, promoting metastatic melanoma progression. These findings suggest the potential utility of KPC1 and its epigenetic regulation as theranostic targets.

from Cancer via ola Kala on Inoreader http://ift.tt/2nN0YQ9
via IFTTT