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Epigenetic Regulation of KPC1 Ubiquitin Ligase Affects the NF-?B Pathway in Melanoma.


ABSTRACT: 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 the 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 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-?B, and the epigenetic regulations of KPC1, including DNA methylation and miRNA 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 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-?B 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.

SUBMITTER: Iida Y 

PROVIDER: S-EPMC5559338 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Epigenetic Regulation of KPC1 Ubiquitin Ligase Affects the NF-κB Pathway in Melanoma.

Iida Yuuki Y   Ciechanover Aaron A   Marzese Diego M DM   Hata Keisuke K   Bustos Matias M   Ono Shigeshi S   Wang Jinhua J   Salomon Matthew P MP   Tran Kevin K   Lam Stella S   Hsu Sandy S   Nelson Nellie N   Kravtsova-Ivantsiv Yelena Y   Mills Gordon B GB   Davies Michael A MA   Hoon Dave S B DSB  

Clinical cancer research : an official journal of the American Association for Cancer Research 20170407 16


<b>Purpose:</b> 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.<b>Experimental Design:</b> The clinical impact of KPC1 expression and its epige  ...[more]

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