Transcriptional repression of IFNβ1 by ATF2 confers melanoma resistance to therapy

• Published in: Oncogene Vol. 34; no. 46; pp. 5739 - 5748
• Main Authors: Lau, E, Sedy, J, Sander, C, Shaw, M A, Feng, Y, Scortegagna, M, Claps, G, Robinson, S, Cheng, P, Srivas, R, Soonthornvacharin, S, Ideker, T, Bosenberg, M, Gonzalez, R, Robinson, W, Chanda, S K, Ware, C, Dummer, R, Hoon, D, Kirkwood, J M, Ronai, Z A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12-11-2015; Nature Publishing Group
• Subjects: 13/51; 38/109; 38/39; 38/77; 45/15; 631/67/1813/1634; 96/95; Activating Transcription Factor 2 - metabolism; Apoptosis; Cell Biology; Cell death; Cell Line, Tumor; Cell Nucleus - metabolism; Chemotherapy; Down-Regulation; Drug resistance; Drug Resistance, Neoplasm; Drug therapy; Gene silencing; Genetic aspects; Health aspects; Human Genetics; Humans; Interferon; Interferon alpha; Interferon-beta - genetics; Internal Medicine; Kinases; Medicine; Medicine & Public Health; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Metastases; Oncology; original-article; Phenotypes; Promoter Regions, Genetic; Protein kinase C; Protein Kinase C-epsilon - metabolism; Senescence; Signal Transduction; Transcription factors; Transcription, Genetic
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.22

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.