Abstract
Mutations in the NRAS oncogene are present in up to 20% of melanoma. Here, we show that interferon alpha-inducible protein 6 (IFI6) is necessary for NRASQ61K-induced transformation and melanoma growth. IFI6 was transcriptionally upregulated by NRASQ61K, and knockdown of IFI6 resulted in DNA replication stress due to dysregulated DNA replication via E2F2. This stress consequentially inhibited cellular transformation and melanoma growth via senescence or apoptosis induction depending on the RB and p53 pathway status of the cells. NRAS-mutant melanoma were significantly more resistant to the cytotoxic effects of DNA replication stress-inducing drugs, and knockdown of IFI6 increased sensitivity to these drugs. Pharmacological inhibition of IFI6 expression by the MEK inhibitor trametinib, when combined with DNA replication stress-inducing drugs, blocked NRAS-mutant melanoma growth. Collectively, we demonstrate that IFI6, via E2F2 regulates DNA replication and melanoma development and growth, and this pathway can be pharmacologically targeted to inhibit NRAS-mutant melanoma.
Highlights
Melanoma is the deadliest form of skin cancer, accounting for ~80% of skin cancer-related deaths (Miller and Mihm, 2006)
We sought to identify factors that are necessary for oncogenic neuroblastoma RAS viral oncogene homolog (NRAS)-induced melanocyte transformation and melanoma growth
We identified three interferon-stimulated genes (ISGs)—interferon alpha-inducible protein 6 (IFI6), IFI27, and MX1—that have not been previously implicated in oncogenic NRAS-induced transformation and melanoma tumor growth (Figure 1A and Figure 1— figure supplement 2)
Summary
Melanoma is the deadliest form of skin cancer, accounting for ~80% of skin cancer-related deaths (Miller and Mihm, 2006). Key pathways regulated by NRAS include the phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), and Ral guanine nucleotide dissociation stimulator (RalGDS) pathways, all of which are shown to play important roles in NRAS-driven oncogenesis (Downward, 2003; Karnoub and Weinberg, 2008). Both the PI3K and MAPK pathways have been targeted using very effective small molecule inhibitors as a clinical approach to treat RAS-mutant cancers, including NRAS-mutant melanoma. New therapeutic approaches for treating NRAS-mutant melanoma and other RAS-mutant cancers are needed
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