Loss of Phd2 cooperates with BRAFV600E to drive melanomagenesis

Shujing Liu, Gao Zhang, Jianping Guo, Xiang Chen, Jingce Lei, Kan Ze, Liyun Dong, Xiangpeng Dai, Yang Gao, Daisheng Song, Brett L. Ecker, Ruifeng Yang, Caitlin Feltcher, Kai Peng, Cheng Feng, Hui Chen, Rebecca X. Lee, Heddy Kerestes, Jingwen Niu, J. Suresh Kumar (), Weiting 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 () and Xiaowei Xu ()
Additional contact information
Shujing Liu: University of Pennsylvania
Gao Zhang: The Wistar Institute
Jianping Guo: Harvard Medical School
Xiang Chen: Central South University
Jingce Lei: University of Pennsylvania
Kan Ze: University of Pennsylvania
Liyun Dong: University of Pennsylvania
Xiangpeng Dai: Harvard Medical School
Yang Gao: Harvard Medical School
Daisheng Song: University of Pennsylvania
Brett L. Ecker: The Wistar Institute
Ruifeng Yang: University of Pennsylvania
Caitlin Feltcher: University of Pennsylvania
Kai Peng: University of Pennsylvania
Cheng Feng: University of Pennsylvania
Hui Chen: University of Pennsylvania
Rebecca X. Lee: University of Pennsylvania
Heddy Kerestes: University of Pennsylvania
Jingwen Niu: University of Pennsylvania
Weiting Xu: New Jersey Institute of Technology
Jie Zhang: New Jersey Institute of Technology
Zhi Wei: New Jersey Institute of Technology
James S. Martin: University of Pennsylvania
Xiaoming Liu: University of Pennsylvania
Gordon Mills: The University of Texas MD Anderson Cancer Center
Yiling Lu: The University of Texas MD Anderson Cancer Center
Wei Guo: University of Pennsylvania
Lunquan Sun: Central South University
Lin Zhang: University of Pennsylvania
Ashani Weeraratna: The Wistar Institute
Meenhard Herlyn: The Wistar Institute
Wenyi Wei: Harvard Medical School
Frank S. Lee: University of Pennsylvania
Xiaowei Xu: University of Pennsylvania

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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 Phd2lox/lox (Tyr::CreER;Phd2lox/lox) fail to develop pigmented lesions. However, deletion of Phd2 in combination with expression of BRafV600E in melanocytes (Tyr::CreER;Phd2lox/lox;BRafCA) 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.

Date: 2018
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DOI: 10.1038/s41467-018-07126-9

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