Document Type
Article
Publication Date
1-2-2018
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.
Recommended Citation
Han, Shujun; Ren, Yibo; He, Wangxiao; Liu, Huadong; Zhi, Zhe; Zhu, Xinliang; Yang, Tielin; Rong, Yu; Ma, Bohan; Purwin, Timothy J.; Ouyang, Zhenlin; Li, Caixia; Wang, Xun; Wang, Xueqiang; Yang, Huizi; Zheng, Yan; Aplin, Andrew E.; Liu, Jiankang; and Shao, Yongping, "ERK-mediated phosphorylation regulates SOX10 sumoylation and targets expression in mutant BRAF melanoma." (2018). Department of Cancer Biology Faculty Papers. Paper 122.
https://jdc.jefferson.edu/cbfp/122
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
29295999
Comments
This article has been peer reviewed. It is the author’s final published version in Nature Communications
Volume 9, Issue 1, January 2018, Article number 2354.
The published version is available at DOI: 10.1038/s41467-017-02354-x. Copyright © Han et al.