Transcriptional repression of IFNβ1 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-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.
Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
E
E
Lau
Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
J
J
Sedy
University of Pittsburgh Cancer Center, Pittsburgh, PA, USA.
C
C
Sander
John Wayne Cancer Institute, Santa Monica, CA, USA.
M A
MA
Shaw
Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
Y
Y
Feng
Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
M
M
Scortegagna
Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
G
G
Claps
Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
S
S
Robinson
Department of Dermatology, University of Zurich, Zurich, Switzerland.
P
P
Cheng
Department of Genetics, Stanford University School of Medicine, Palo Alto, CA, USA.
R
R
Srivas
Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
S
S
Soonthornvacharin
Department of Medicine, University of California, San Diego, San Diego, CA, USA.
T
T
Ideker
Yale School of Medicine, New Haven, CT, USA.
M
M
Bosenberg
Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
R
R
Gonzalez
Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
W
W
Robinson
Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
S K
SK
Chanda
Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
C
C
Ware
Department of Dermatology, University of Zurich, Zurich, Switzerland.
R
R
Dummer
John Wayne Cancer Institute, Santa Monica, CA, USA.
D
D
Hoon
University of Pittsburgh Cancer Center, Pittsburgh, PA, USA.
J M
JM
Kirkwood
Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
Z A
ZA
Ronai
D051698:Activating Transcription Factor 2 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D006801:Humans; D016899:Interferon-beta / Q000235:genetics*; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D016899:Interferon-beta; C497255:PRKCE protein, human; D051744:Protein Kinase C-epsilon