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

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Listed:
  • 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
    Thomas Jefferson University)

  • Jiankang Liu

    (School of Life Science and Technology, Xi’an Jiaotong University
    Xi’an Jiaotong University
    Tianjin University of Sport)

  • Yongping Shao

    (School of Life Science and Technology, Xi’an Jiaotong University)

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.

Suggested Citation

  • 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 &, 2018. "ERK-mediated phosphorylation regulates SOX10 sumoylation and targets expression in mutant BRAF melanoma," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02354-x
    DOI: 10.1038/s41467-017-02354-x
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    Cited by:

    1. Claudia Capparelli & Timothy J. Purwin & McKenna Glasheen & Signe Caksa & Manoela Tiago & Nicole Wilski & Danielle Pomante & Sheera Rosenbaum & Mai Q. Nguyen & Weijia Cai & Janusz Franco-Barraza & Ric, 2022. "Targeting SOX10-deficient cells to reduce the dormant-invasive phenotype state in melanoma," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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