Transcriptional repression of IFNβ1 by ATF2 confers melanoma resistance to therapy

Oncogene
Eric LauZe'ev A Ronai

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 re...Continue Reading

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Citations

Apr 22, 2017·Experimental Biology and Medicine·Xiang SunLijuan Wan
Jun 2, 2020·Journal of Cellular and Molecular Medicine·Fushi HanShuzhen Chen
Mar 3, 2020·Frontiers in Immunology·Eric D RouthLance D Miller
Dec 11, 2020·Cancer Cell International·Jian LiuYamei Pang

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Methods Mentioned

BETA
immunoprecipitation
ChIP
FACS
transfection
fluorescence activated cell sorting

Software Mentioned

FlowJo

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