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Loss of Phd2 cooperates with BRAFV600E to drive melanomagenesis

Author

Listed:
  • 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)

  • Suresh Kumar

    (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)

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.

Suggested Citation

  • 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 , 2018. "Loss of Phd2 cooperates with BRAFV600E to drive melanomagenesis," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07126-9
    DOI: 10.1038/s41467-018-07126-9
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