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

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 epsilon (PKCε)- and Activating Transcription Factor-2 (ATF2)-mediated mechanism that facilitates resistance by transcriptionally repressing the expression of IFNβ1 and downstream type-I IFN signaling, which is otherwise induced upon exposure to chemotherapy. Treatment of early stage melanomas expressing low levels of PKCε with chemotherapies relieves its transcriptional repression of IFNB1, 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 PKCε. 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 PKCε-ATF2 regulatory axis.