Epigenetic regulation of KPC1 ubiquitin ligase affects the NF-κB pathway in melanoma

Yuuki Iida, Aaron Ciechanover, Diego M. Marzese, Keisuke Hata, Matias Bustos, Shigeshi Ono, Jinhua Wang, Matthew P. Salomon, Kevin Tran, Stella Lam, Sandy Hsu, Nellie Nelson, Yelena Kravtsova-Ivantsiv, Gordon Mills, Michael A. Davies, Dave S.B. Hoon

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4831-4842
Number of pages12
JournalClinical Cancer Research
Volume23
Issue number16
DOIs
StatePublished - Aug 15 2017
Externally publishedYes

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Ligases
Ubiquitin
Epigenomics
Melanoma
NF-kappa B
DNA Methylation
Down-Regulation
Ubiquitin-Protein Ligases
Atlases
MicroRNAs
Genetic Promoter Regions
Neoplasms
Research Design
Genome
Databases
Phenotype
Gene Expression
Cell Line
Skin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Iida, Y., Ciechanover, A., Marzese, D. M., Hata, K., Bustos, M., Ono, S., ... Hoon, D. S. B. (2017). Epigenetic regulation of KPC1 ubiquitin ligase affects the NF-κB pathway in melanoma. Clinical Cancer Research, 23(16), 4831-4842. https://doi.org/10.1158/1078-0432.CCR-17-0146

Epigenetic regulation of KPC1 ubiquitin ligase affects the NF-κB pathway in melanoma. / 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; Davies, Michael A.; Hoon, Dave S.B.

In: Clinical Cancer Research, Vol. 23, No. 16, 15.08.2017, p. 4831-4842.

Research output: Contribution to journalArticle

Iida, Y, Ciechanover, A, Marzese, DM, Hata, K, Bustos, M, Ono, S, Wang, J, Salomon, MP, Tran, K, Lam, S, Hsu, S, Nelson, N, Kravtsova-Ivantsiv, Y, Mills, G, Davies, MA & Hoon, DSB 2017, 'Epigenetic regulation of KPC1 ubiquitin ligase affects the NF-κB pathway in melanoma', Clinical Cancer Research, vol. 23, no. 16, pp. 4831-4842. https://doi.org/10.1158/1078-0432.CCR-17-0146
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 ; Davies, Michael A. ; Hoon, Dave S.B. / Epigenetic regulation of KPC1 ubiquitin ligase affects the NF-κB pathway in melanoma. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 16. pp. 4831-4842.
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title = "Epigenetic regulation of KPC1 ubiquitin ligase affects the NF-κB pathway in melanoma",
abstract = "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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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

AU - Davies, Michael A.

AU - Hoon, Dave S.B.

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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