ZIC5 Drives Melanoma Aggressiveness by PDGFD-Mediated Activation of FAK and STAT3.
Insights into mechanisms of drug resistance could extend the efficacy of cancer therapy. To probe mechanisms in melanoma, we performed siRNA screening of genes that mediate the development of neural crest cells, from which melanocytes are derived. Here, we report the identification of ZIC5 as a mediator of melanoma drug resistance. ZIC5 is a transcriptional suppressor of E-cadherin expressed highly in human melanoma. ZIC5 enhanced melanoma cell proliferation, survival, drug resistance, in vivo growth and metastasis. Microarray analysis revealed that ZIC5 downstream signaling included PDGFD and FAK activation, which contributes to drug resistance by enhancing STAT3 activation. Silencing of ZIC5 or PDGFD enhanced the apoptotic effects of BRAF inhibition and blocked survival of melanoma cells resistant to BRAF inhibitors. Furthermore, inhibition of FAK or STAT3 suppressed expression of ZIC5, which was positively regulated by PDGFD, FAK, and STAT3 in a positive feedback loop. Taken together, our results identify ZIC5 and PDGFD as candidate therapeutic targets to overcome drug resistance in melanoma. Cancer Res; 77(2); 366-77. ©2016 AACR.
Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Sciences, Hachioji-shi, Tokyo, Japan.|AMED-CREST, Japan Agency for Medical Research and Development, Hachioji-shi, Tokyo, Japan.
Reiko
R
Satow
Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Sciences, Hachioji-shi, Tokyo, Japan.
Tomomi
T
Nakamura
Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Sciences, Hachioji-shi, Tokyo, Japan.
Chiaki
C
Kato
Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Sciences, Hachioji-shi, Tokyo, Japan.
Miku
M
Endo
Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Sciences, Hachioji-shi, Tokyo, Japan.
Mana
M
Tamura
Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Sciences, Hachioji-shi, Tokyo, Japan.
Ryosuke
R
Batori
Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Sciences, Hachioji-shi, Tokyo, Japan.
Shiori
S
Tomura
Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Sciences, Hachioji-shi, Tokyo, Japan.
Yumi
Y
Murayama
Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Sciences, Hachioji-shi, Tokyo, Japan. kfukami@toyaku.ac.jp.|AMED-CREST, Japan Agency for Medical Research and Development, Hachioji-shi, Tokyo, Japan.
Kiyoko
K
Fukami
D015153:Blotting, Western; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D008222:Lymphokines / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D008222:Lymphokines; C427493:PDGFD protein, human; D010982:Platelet-Derived Growth Factor; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014157:Transcription Factors; C485965:ZIC5 protein, human; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human