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Publication Detail

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

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

Published In Oncogene, (2015 Nov 12)

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.

PubMed ID: 25728676 Exiting the NIEHS site

MeSH Terms: Activating Transcription Factor 2/metabolism*; Cell Line, Tumor; Cell Nucleus/metabolism; Down-Regulation; Drug Resistance, Neoplasm*; Humans; Interferon-beta/genetics*; Melanoma/drug therapy; Melanoma/genetics*; Melanoma/metabolism; Melanoma/pathology; Promoter Regions, Genetic; Protein Kinase C-epsilon/metabolism; Signal Transduction; Transcription, Genetic

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