Portal de Periódicos da CAPES

MELK Promotes Melanoma Growth by Stimulating the NF-κB Pathway

2017; Cell Press; Volume: 21; Issue: 10 Linguagem: Inglês

10.1016/j.celrep.2017.11.033

2639-1856

Radoslav Janoštiak, Navin Rauniyar, TuKiet T. Lam, Jianhong Ou, Lihua Julie Zhu, Michael R. Green, Narendra Wajapeyee,

RNA regulation and disease

Highlights•MELK is upregulated in melanoma by the MAPK pathway via E2F1•MELK inhibition blocks melanoma growth•MELK phosphorylates a large number of BRAF and MEK substrates•MELK partly promotes melanoma by stimulating the NF-κB pathway via SQSTM1SummaryMelanoma 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.Graphical abstract