NF-κB inducing kinase (NIK) modulates melanoma tumorigenesis by regulating expression of pro-survival factors through the β-catenin pathway.

Thu YM, Su Y, Yang J, Splittgerber R, Na S, Boyd A, Mosse C, Simons C, Richmond A
Oncogene. 2012 31 (20): 2580-92

PMID: 21963849 · PMCID: PMC3253179 · DOI:10.1038/onc.2011.427

Nuclear factor-κB (NF-κB) inducing kinase (NIK) is a MAP3K that regulates the activation of NF-κB. NIK is often highly expressed in tumor cells, including melanoma, but the significance of this in melanoma progression has been unclear. Tissue microarray analysis of NIK expression reveals that dysplastic nevi (n=22), primary (n=15) and metastatic melanoma (n=13) lesions showed a statistically significant elevation in NIK expression when compared with benign nevi (n=30). Moreover, when short hairpin RNA techniques were used to knock-down NIK, the resultant NIK-depleted melanoma cell lines exhibited decreased proliferation, increased apoptosis, delayed cell cycle progression and reduced tumor growth in a mouse xenograft model. As expected, when NIK was depleted there was decreased activation of the non-canonical NF-κB pathway, whereas canonical NF-κB activation remained intact. NIK depletion also resulted in reduced expression of genes that contribute to tumor growth, including CXCR4, c-MYC and c-MET, and pro-survival factors such as BCL2 and survivin. These changes in gene expression are not fully explained by the attenuation of the non-canonical NF-κB pathway. Shown here for the first time is the demonstration that NIK modulates β-catenin-mediated transcription to promote expression of survivin. NIK-depleted melanoma cells exhibited downregulation of survivin as well as other β-catenin regulated genes including c-MYC, c-MET and CCND2. These data indicate that NIK mediates both β-catenin and NF-κB regulated transcription to modulate melanoma survival and growth. Thus, NIK may be a promising therapeutic target for melanoma.

MeSH Terms (21)

Animals Apoptosis beta Catenin Cell Line, Tumor Cell Proliferation Cell Survival Cyclin D2 Down-Regulation Enzyme Activation Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Genes, bcl-2 Genes, myc Humans Melanoma Melanoma, Experimental Mice Neoplasm Metastasis Protein-Serine-Threonine Kinases RNA, Small Interfering Signal Transduction

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