Interferon alpha-inducible protein 6 regulates NRASQ61K-induced melanomagenesis and growth.
Mutations in theNRASoncogene 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.IFI6was transcriptionally upregulated by NRASQ61K, and knockdown ofIFI6resulted 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 ofIFI6increased sensitivity to these drugs. Pharmacological inhibition ofIFI6expression 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.
Department of Pathology, Yale University School of Medicine, New Haven, United States.
Romi
R
Gupta
Department of Pathology, Yale University School of Medicine, New Haven, United States.
Matteo
M
Forloni
Department of Pathology, Yale University School of Medicine, New Haven, United States.
Malik
M
Bisserier
Singapore Institute of Clinical Sciences, Agency for Science Technology and Research (A*STAR), Brenner Center for Molecular Medicine, Singapore, Singapore.
Shaillay Kumar
SK
Dogra
Department of Pathology, Yale University School of Medicine, New Haven, United States.
Qiaohong
Q
Yang
Department of Pathology, Yale University School of Medicine, New Haven, United States.
Narendra
http://orcid.org/0000-0003-3306-349X
N
Wajapeyee
DNA replication; RAS; cancer biology; human; melanoma