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Transcriptional repression of IFNβ1 by ATF2 confers melanoma resistance to therapy

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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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Acknowledgements

We thank Serge Fuchs (UPENN) and members of the Ronai laboratory for crucial scientific discussions and critical reading of this manuscript. Additional thanks to Mitch Levesque and Valerie Amann for their assistance in providing patient samples from the Department of Dermatology, University of Zurich. We are grateful to Jian-Liang Li of the SBMRI Bioinformatics Core, as well as the SBMRI Flow Cytometry and Histology Core, for technical support. Support from NCI P01 (CA128814), R01 (CA179170), Hervey Family Non-endowment Fund at The San Diego Foundation and a Melanoma Research Foundation grant to ZAR are gratefully acknowledged. Support from NCI Grants R01 (CA164679) and P01 (CA177322) to CW and P50 SPORE (CA121973) to JMK is also gratefully acknowledged. EL has been supported by K99 (CA172705) and T32 (CA121949) Grants.

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Correspondence to E Lau or Z A Ronai.

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Lau, E., Sedy, J., Sander, C. et al. Transcriptional repression of IFNβ1 by ATF2 confers melanoma resistance to therapy. Oncogene 34, 5739–5748 (2015). https://doi.org/10.1038/onc.2015.22

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