Loss of Phd2 cooperates with BRAF V600E to drive melanomagenesis

Shujing Liu, Gao Zhang, Jianping Guo, Xiang Chen, Jingce Lei, Kan Ze, Liyun Dong, Xiangpeng Dai, Yang Gao, Daisheng Song, Brett Ecker, Ruifeng Yang, Caitlin Feltcher, Kai Peng, Cheng Feng, Hui Chen, Rebecca X. Lee, Heddy Kerestes, Jingwen Niu, Suresh KumarWeiting Xu, Jie Zhang, Zhi Wei, James S. Martin, Xiaoming Liu, Gordon Mills, Yiling Lu, Wei Guo, Lunquan Sun, Lin Zhang, Ashani Weeraratna, Meenhard Herlyn, Wenyi Wei, Frank S. Lee, Xiaowei Xu

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Prolyl hydroxylase domain protein 2 (PHD2) is a well-known master oxygen sensor. However, the role of PHD2 in tumor initiation remains controversial. We find that during the transition of human nevi to melanoma, the expression of PHD2 protein is significantly decreased and lower expression PHD2 in melanoma is associated with worse clinical outcome. Knockdown of PHD2 leads to elevated Akt phosphorylation in human melanocytes. Mice with conditional melanocyte-specific expression of Phd2 lox/lox (Tyr::CreER;Phd2 lox/lox ) fail to develop pigmented lesions. However, deletion of Phd2 in combination with expression of BRaf V600E in melanocytes (Tyr::CreER;Phd2 lox/lox ;BRaf CA ) leads to the development of melanoma with 100% penetrance and frequent lymph node metastasis. Analysis of tumor tissues using reverse phase protein arrays demonstrates that Phd2 deletion activates the AKT-mTOR-S6 signaling axis in the recovered tumors. These data indicate that PHD2 is capable of suppressing tumor initiation largely mediated through inhibiting of the Akt-mTOR signaling pathway in the melanocyte lineage.

Original languageEnglish (US)
Article number5426
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018
Externally publishedYes

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Liu, S., Zhang, G., Guo, J., Chen, X., Lei, J., Ze, K., Dong, L., Dai, X., Gao, Y., Song, D., Ecker, B., Yang, R., Feltcher, C., Peng, K., Feng, C., Chen, H., Lee, R. X., Kerestes, H., Niu, J., ... Xu, X. (2018). Loss of Phd2 cooperates with BRAF V600E to drive melanomagenesis Nature Communications, 9(1), [5426]. https://doi.org/10.1038/s41467-018-07126-9