Interferon Alpha-Inducible Protein 6 regulates NRASQ61K-induced melanomagenesis and growth
- Yale University School of Medicine, United States
- Agency for Science Technology and Research, Singapore
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.
Data availability
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Transcriptional targets of oncogenic RAS proteins that mediate their ability to induce cellular transformationPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE62827).
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Regulators of NRAS-mediated transformation and melanoma tumor maintenancePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE69933).
Article and author information
Author details
Narendra Wajapeyee
Funding
National Institutes of Health (R01CA200919)
- Narendra Wajapeyee
National Institutes of Health (R21CA195077-01A1)
- Narendra Wajapeyee
National Institutes of Health (R21CA191364-01)
- Narendra Wajapeyee
National Institutes of Health (R21CA197758-01)
- Narendra Wajapeyee
Melanoma Research Alliance (Pilot grant award)
- Narendra Wajapeyee
National Institutes of Health (R01CA196566)
- Narendra Wajapeyee
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the Yale University (IACUC protocol #2016-11333).
Copyright
© 2016, Gupta et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Interferon Alpha-Inducible Protein 6 regulates NRASQ61K-induced melanomagenesis and growth
eLife 5:e16432.
https://doi.org/10.7554/eLife.16432
Further reading
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