Loss of Phd2 cooperates with BRAF V600E to drive melanomagenesis

Authors

Shujing Liu, University of Pennsylvania Perelman School of Medicine
Gao Zhang, The Wistar Institute
Jianping Guo, Harvard Medical School
Xiang Chen, Central South University
Jingce Lei, University of Pennsylvania Perelman School of Medicine
Kan Ze, University of Pennsylvania Perelman School of Medicine
Liyun Dong, University of Pennsylvania Perelman School of Medicine
Xiangpeng Dai, Harvard Medical School
Yang Gao, Harvard Medical School
Daisheng Song, University of Pennsylvania Perelman School of Medicine
Brett Ecker, The Wistar Institute
Ruifeng Yang, University of Pennsylvania Perelman School of Medicine
Caitlin Feltcher, University of Pennsylvania Perelman School of Medicine
Kai Peng, University of Pennsylvania Perelman School of Medicine
Cheng Feng, University of Pennsylvania Perelman School of Medicine
Hui Chen, University of Pennsylvania Perelman School of Medicine
Rebecca X. Lee, University of Pennsylvania Perelman School of Medicine
Heddy Kerestes, University of Pennsylvania Perelman School of Medicine

Document Type

Article

Publication Date

12-1-2018

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.

Identifier

85058914608 (Scopus)

Publication Title

Nature Communications

External Full Text Location

https://doi.org/10.1038/s41467-018-07126-9

e-ISSN

20411723

PubMed ID

30575721

Issue

1

Volume

9

Grant

P01CA025874

Fund Ref

National Institutes of Health

Recommended Citation

Liu, Shujing; Zhang, Gao; Guo, Jianping; Chen, Xiang; Lei, Jingce; Ze, Kan; Dong, Liyun; Dai, Xiangpeng; Gao, Yang; Song, Daisheng; Ecker, Brett; Yang, Ruifeng; Feltcher, Caitlin; Peng, Kai; Feng, Cheng; Chen, Hui; Lee, Rebecca X.; and Kerestes, Heddy, "Loss of Phd2 cooperates with BRAF V600E to drive melanomagenesis" (2018). Faculty Publications. 8235.
https://digitalcommons.njit.edu/fac_pubs/8235