TY - JOUR
T1 - Epigenetic regulation of KPC1 ubiquitin ligase affects the NF-κB pathway in melanoma
AU - Iida, Yuuki
AU - Ciechanover, Aaron
AU - Marzese, Diego M.
AU - Hata, Keisuke
AU - Bustos, Matias
AU - Ono, Shigeshi
AU - Wang, Jinhua
AU - Salomon, Matthew P.
AU - Tran, Kevin
AU - Lam, Stella
AU - Hsu, Sandy
AU - Nelson, Nellie
AU - Kravtsova-Ivantsiv, Yelena
AU - Mills, Gordon B.
AU - Davies, Michael A.
AU - Hoon, Dave S.B.
N1 - Funding Information:
The authors thank Ms. Nousha Javanmardi and Dr. Ian V Hutchinson for their editorial assistance and Department of Translational Molecular Medicine Staff from Division of Molecular Oncology (JWCI), for their kind advisory and technical assistance. This work was supported by the NIH, National Cancer Institute (R01CA167967 to D.S.B. Hoon), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to D.S.B. Hoon, A. Ciechanover), the Leslie and Susan Gonda (Goldschmied) Foundation (to D.S.B. Hoon), the Israel Science Foundation (to A. Ciechanover), and the I-CORE Program of the Planning and Budgeting Committee (Grant no. 1775/12 to A. Ciechanover). The RPPA analysis was supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to G.B. Mills and M.A. Davies) and the FHCRC/UW Cancer Consortium Cancer Center Support Grant of the National Institutes of Health (P30 CA016672 to G.B. Mills). The RPPA Core Facility was supported by NIH, National Cancer Institute (CA16672 to M.A. Davies). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Funding Information:
This work was supported by the NIH, National Cancer Institute (R01CA167967 to D.S.B. Hoon), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to D.S.B. Hoon, A. Ciechanover), the Leslie and Susan Gonda (Goldschmied) Foundation (to D.S.B. Hoon), the Israel Science Foundation (to A. Ciechanover), and the I-CORE Program of the Planning and Budgeting Committee (Grant no. 1775/12 to A. Ciechanover). The RPPA analysis was supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to G.B. Mills and M.A. Davies) and the FHCRC/UW Cancer Consortium Cancer Center Support Grant of the National Institutes of Health (P30 CA016672 to G.B. Mills). The RPPA Core Facility was supported by NIH, National Cancer Institute (CA16672 to M.A. Davies).
Publisher Copyright:
©2017 AACR.
PY - 2017/8/15
Y1 - 2017/8/15
N2 - Purpose: Abnormal activation of the NF-kB pathway induces a more aggressive phenotype of cutaneous melanoma. Understanding the mechanisms involved in melanoma NF-kB activation may identify novel targets for this pathway. KPC1, an E3 ubiquitin ligase, is a regulator of the NF-kB 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 ¼ 137, JWCI cohort; n ¼ 40) and The Cancer Genome Atlas database (TCGA cohort, n ¼ 370). Using melanoma cell lines, we investigated the functional interactions between KPC1 and NF-kB, and the epigenetic regulations of KPC1, including DNA methylation and miRNA expression. Results: We verified that KPC1 suppresses melanoma proliferation by processing NF-kB1 p105 into p50, thereby modulating NF-kB 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 ¼ 0.013, stage III P ¼ 0.004), and low KPC1 expression was significantly associated with poor overall survival in stage IV melanoma (n ¼ 137; HR 1.810; P ¼ 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 ¼ 0.028, TCGA; P ¼ 0.003). Conclusions: This study revealed novel epigenetic regulation of KPC1 associated with NF-kB pathway activation, promoting metastatic melanoma progression. These findings suggest the potential utility of KPC1 and its epigenetic regulation as theranostic targets.
AB - Purpose: Abnormal activation of the NF-kB pathway induces a more aggressive phenotype of cutaneous melanoma. Understanding the mechanisms involved in melanoma NF-kB activation may identify novel targets for this pathway. KPC1, an E3 ubiquitin ligase, is a regulator of the NF-kB 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 ¼ 137, JWCI cohort; n ¼ 40) and The Cancer Genome Atlas database (TCGA cohort, n ¼ 370). Using melanoma cell lines, we investigated the functional interactions between KPC1 and NF-kB, and the epigenetic regulations of KPC1, including DNA methylation and miRNA expression. Results: We verified that KPC1 suppresses melanoma proliferation by processing NF-kB1 p105 into p50, thereby modulating NF-kB 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 ¼ 0.013, stage III P ¼ 0.004), and low KPC1 expression was significantly associated with poor overall survival in stage IV melanoma (n ¼ 137; HR 1.810; P ¼ 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 ¼ 0.028, TCGA; P ¼ 0.003). Conclusions: This study revealed novel epigenetic regulation of KPC1 associated with NF-kB pathway activation, promoting metastatic melanoma progression. These findings suggest the potential utility of KPC1 and its epigenetic regulation as theranostic targets.
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U2 - 10.1158/1078-0432.CCR-17-0146
DO - 10.1158/1078-0432.CCR-17-0146
M3 - Article
C2 - 28389511
AN - SCOPUS:85028080866
SN - 1078-0432
VL - 23
SP - 4831
EP - 4842
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -