1. Cancer Biology
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Interferon Alpha-Inducible Protein 6 regulates NRASQ61K-induced melanomagenesis and growth

  1. Romi Gupta
  2. Matteo Forloni
  3. Malik Bisseier
  4. Shaillay Kumar Dogra
  5. Qiahong Yang
  6. Narendra Wajapeyee  Is a corresponding author
  1. Yale University School of Medicine, United States
  2. Agency for Science Technology and Research, Singapore
Research Article
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Cite this article as: eLife 2016;5:e16432 doi: 10.7554/eLife.16432

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.

Article and author information

Author details

  1. Romi Gupta

    Department of Pathology, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Matteo Forloni

    Department of Pathology, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Malik Bisseier

    Department of Pathology, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Shaillay Kumar Dogra

    Singapore Institute of Clinical Sciences, Agency for Science Technology and Research, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  5. Qiahong Yang

    Department of Pathology, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Narendra Wajapeyee

    Department of Pathology, Yale University School of Medicine, New Haven, United States
    For correspondence
    narendra.wajapeyee@yale.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3306-349X

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).

Reviewing Editor

  1. Joaquín M Espinosa, University of Colorado School of Medicine, United States

Publication history

  1. Received: March 28, 2016
  2. Accepted: September 7, 2016
  3. Accepted Manuscript published: September 8, 2016 (version 1)
  4. Version of Record published: September 21, 2016 (version 2)

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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