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Oncogene. 2015 Nov 12;34(46):5739-48. doi: 10.1038/onc.2015.22. Epub 2015 Mar 2.

Transcriptional repression of IFNβ1 by ATF2 confers melanoma resistance to therapy.

Author information

1
Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
2
University of Pittsburgh Cancer Center, Pittsburgh, PA, USA.
3
John Wayne Cancer Institute, Santa Monica, CA, USA.
4
Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
5
Department of Dermatology, University of Zurich, Zurich, Switzerland.
6
Department of Genetics, Stanford University School of Medicine, Palo Alto, CA, USA.
7
Department of Medicine, University of California, San Diego, San Diego, CA, USA.
8
Yale School of Medicine, New Haven, CT, USA.

Abstract

The resistance of melanoma to current treatment modalities represents a major obstacle for durable therapeutic response, and thus the elucidation of mechanisms of resistance is urgently needed. The crucial functions of activating transcription factor-2 (ATF2) in the development and therapeutic resistance of melanoma have been previously reported, although the precise underlying mechanisms remain unclear. Here, we report a protein kinase C-ɛ (PKCɛ)- and ATF2-mediated mechanism that facilitates resistance by transcriptionally repressing the expression of interferon-β1 (IFNβ1) and downstream type-I IFN signaling that is otherwise induced upon exposure to chemotherapy. Treatment of early-stage melanomas expressing low levels of PKCɛ with chemotherapies relieves ATF2-mediated transcriptional repression of IFNβ1, resulting in impaired S-phase progression, a senescence-like phenotype and increased cell death. This response is lost in late-stage metastatic melanomas expressing high levels of PKCɛ. Notably, nuclear ATF2 and low expression of IFNβ1 in melanoma tumor samples correlates with poor patient responsiveness to biochemotherapy or neoadjuvant IFN-α2a. Conversely, cytosolic ATF2 and induction of IFNβ1 coincides with therapeutic responsiveness. Collectively, we identify an IFNβ1-dependent, cell-autonomous mechanism that contributes to the therapeutic resistance of melanoma via the PKCɛ-ATF2 regulatory axis.

PMID:
25728676
PMCID:
PMC4558399
DOI:
10.1038/onc.2015.22
[Indexed for MEDLINE]
Free PMC Article

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