Transcriptional repression of IFN[beta]1 by ATF2 confers melanoma resistance to therapy

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- (PKC)- and ATF2-mediated mechanism that facilitates resistance by transcriptionally repressing the expression of interferon-1 (IFN1) and downstream type-I IFN signaling that is otherwise induced upon exposure to chemotherapy. Treatment of early-stage melanomas expressing low levels of PKC with chemotherapies relieves ATF2-mediated transcriptional repression of IFN1, 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 PKC. Notably, nuclear ATF2 and low expression of IFN1 in melanoma tumor samples correlates with poor patient responsiveness to biochemotherapy or neoadjuvant IFN-2a. Conversely, cytosolic ATF2 and induction of IFN1 coincides with therapeutic responsiveness. Collectively, we identify an IFN1-dependent, cell-autonomous mechanism that contributes to the therapeutic resistance of melanoma via the PKCATF2 regulatory axis.