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Cell Rep. 2017 Dec 5;21(10):2829-2841. doi: 10.1016/j.celrep.2017.11.033.

MELK Promotes Melanoma Growth by Stimulating the NF-κB Pathway.

Author information

1
Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
2
Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06510, USA; MS and Proteomics Resource, W.M. Keck Foundation Biotechnology Resource Laboratory, Yale University School of Medicine, New Haven, CT 06510, USA.
3
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
4
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Howard Hughes Medical Institute, Worcester, MA 01605, USA.
5
Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: narendra.wajapeyee@yale.edu.

Abstract

Melanoma accounts for more than 80% of skin cancer-related deaths, and current therapies provide only short-term benefit to patients. Here, we show in melanoma cells that maternal embryonic leucine zipper kinase (MELK) is transcriptionally upregulated by the MAPK pathway via transcription factor E2F1. MELK knockdown or pharmacological inhibition blocked melanoma growth and enhanced the effectiveness of BRAFV600E inhibitor against melanoma cells. To identify mediators of MELK function, we performed stable isotope labeling with amino acids in cell culture (SILAC) and identified 469 proteins that had downregulated phosphorylation after MELK inhibition. Of these proteins, 139 were previously reported as substrates of BRAF or MEK, demonstrating that MELK is an important downstream mediator of the MAPK pathway. Furthermore, we show that MELK promotes melanoma growth by activating NF-κB pathway activity via Sequestosome 1 (SQSTM1/p62). Altogether, these results underpin an important role for MELK in melanoma growth downstream of the MAPK pathway.

KEYWORDS:

BRAF; MELK; NF-κB; SILAC; SQSTM1; melanoma

PMID:
29212029
PMCID:
PMC5726781
DOI:
10.1016/j.celrep.2017.11.033
[Indexed for MEDLINE]
Free PMC Article

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