ERK-mediated phosphorylation regulates SOX10 sumoylation and targets expression in mutant BRAF melanoma

Shujun Han, Yibo Ren, Wangxiao He, Huadong Liu, Zhe Zhi, Xinliang Zhu, Tielin Yang, Yu Rong, Bohan Ma, Timothy J. Purwin, Zhenlin Ouyang, Caixia Li, Xun Wang, Xueqiang Wang, Huizi Yang, Yan Zheng, Andrew E. Aplin, Jiankang Liu () and Yongping Shao ()
Additional contact information
Shujun Han: School of Life Science and Technology, Xi’an Jiaotong University
Yibo Ren: School of Life Science and Technology, Xi’an Jiaotong University
Wangxiao He: School of Life Science and Technology, Xi’an Jiaotong University
Huadong Liu: School of Life Science and Technology, Xi’an Jiaotong University
Zhe Zhi: School of Life Science and Technology, Xi’an Jiaotong University
Xinliang Zhu: School of Life Science and Technology, Xi’an Jiaotong University
Tielin Yang: School of Life Science and Technology, Xi’an Jiaotong University
Yu Rong: School of Life Science and Technology, Xi’an Jiaotong University
Bohan Ma: School of Life Science and Technology, Xi’an Jiaotong University
Timothy J. Purwin: Thomas Jefferson University
Zhenlin Ouyang: School of Life Science and Technology, Xi’an Jiaotong University
Caixia Li: School of Life Science and Technology, Xi’an Jiaotong University
Xun Wang: School of Life Science and Technology, Xi’an Jiaotong University
Xueqiang Wang: School of Life Science and Technology, Xi’an Jiaotong University
Huizi Yang: School of Life Science and Technology, Xi’an Jiaotong University
Yan Zheng: the Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University
Andrew E. Aplin: Thomas Jefferson University
Jiankang Liu: School of Life Science and Technology, Xi’an Jiaotong University
Yongping Shao: School of Life Science and Technology, Xi’an Jiaotong University

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract In human mutant BRAF melanoma cells, the stemness transcription factor FOXD3 is rapidly induced by inhibition of ERK1/2 signaling and mediates adaptive resistance to RAF inhibitors. However, the mechanism underlying ERK signaling control of FOXD3 expression remains unknown. Here we show that SOX10 is both necessary and sufficient for RAF inhibitor-induced expression of FOXD3 in mutant BRAF melanoma cells. SOX10 activates the transcription of FOXD3 by binding to a regulatory element in FOXD3 promoter. Phosphorylation of SOX10 by ERK inhibits its transcription activity toward multiple target genes by interfering with the sumoylation of SOX10 at K55, which is essential for its transcription activity. Finally, depletion of SOX10 sensitizes mutant BRAF melanoma cells to RAF inhibitors in vitro and in vivo. Thus, our work discovers a novel phosphorylation-dependent regulatory mechanism of SOX10 transcription activity and completes an ERK1/2/SOX10/FOXD3/ERBB3 axis that mediates adaptive resistance to RAF inhibitors in mutant BRAF melanoma cells.

Date: 2018
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DOI: 10.1038/s41467-017-02354-x

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