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

Authors
  • E, Lau
  • J, Sedy
  • C, Sander
  • Ma, Shaw
  • Y, Feng
  • M, Scortegagna
  • G, Claps
  • S, Robinson
  • P, Cheng
  • R, Srivas
  • S, Soonthornvacharin
  • Trey Ideker
  • M, Bosenberg
  • R, Gonzalez
  • W, Robinson
  • Sk, Chanda
  • C, Ware
  • R, Dummer
  • D, Hoon
  • Jm, Kirkwood
  • And 1 more
Type
Published Article
Journal
Oncogene
Publisher
Springer Nature
Volume
34
Issue
46
Pages
5739–5748
Identifiers
DOI: 10.1038/onc.2015.22
Source
Ideker Lab
License
Unknown

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.

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