MELK Promotes Melanoma Growth by Stimulating the NF-κB Pathway
Radoslav Janostiak,
Navin Rauniyar,
TuKiet T. Lam,
Jianhong Ou,
Lihua J. Zhu,
Michael R. Green,
Narendra Wajapeyee
Affiliations
Radoslav Janostiak
Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA
Navin Rauniyar
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
TuKiet T. Lam
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
Jianhong Ou
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Lihua J. Zhu
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Michael R. Green
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Howard Hughes Medical Institute, Worcester, MA 01605, USA
Narendra Wajapeyee
Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA; Corresponding author
Summary: 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. : Janostiak et al. find that MELK is overexpressed in melanoma and is necessary for melanoma growth. MELK regulates the NF-κB pathway via SQSTM1, which is necessary partly for its ability to promote melanoma growth. Keywords: MELK, melanoma, BRAF, SILAC, NF-κB, SQSTM1
