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Nuclear lactate dehydrogenase A senses ROS to produce α-hydroxybutyrate for HPV-induced cervical tumor growth

Author

Listed:
  • Yuan Liu

    (Sichuan University, and Collaborative Innovation Center for Biotherapy)

  • Ji-Zheng Guo

    (Fudan University
    Fudan University)

  • Ying Liu

    (Fudan University)

  • Kui Wang

    (Sichuan University, and Collaborative Innovation Center for Biotherapy)

  • Wencheng Ding

    (Huazhong University of Science and Technology)

  • Hui Wang

    (Huazhong University of Science and Technology)

  • Xiang Liu

    (Sichuan Provincial People’s Hospital)

  • Shengtao Zhou

    (Sichuan University)

  • Xiao-Chen Lu

    (Fudan University)

  • Hong-Bin Yang

    (Fudan University)

  • Chenyue Xu

    (Fudan University)

  • Wei Gao

    (Sichuan University, and Collaborative Innovation Center for Biotherapy)

  • Li Zhou

    (Sichuan University, and Collaborative Innovation Center for Biotherapy)

  • Yi-Ping Wang

    (Fudan University)

  • Weiguo Hu

    (Fudan University)

  • Yuquan Wei

    (Sichuan University)

  • Canhua Huang

    (Sichuan University, and Collaborative Innovation Center for Biotherapy)

  • Qun-Ying Lei

    (Fudan University
    Fudan University)

Abstract

It is well known that high-risk human papilloma virus (HR-HPV) infection is strongly associated with cervical cancer and E7 was identified as one of the key initiators in HPV-mediated carcinogenesis. Here we show that lactate dehydrogenase A (LDHA) preferably locates in the nucleus in HPV16-positive cervical tumors due to E7-induced intracellular reactive oxygen species (ROS) accumulation. Surprisingly, nuclear LDHA gains a non-canonical enzyme activity to produce α-hydroxybutyrate and triggers DOT1L (disruptor of telomeric silencing 1-like)-mediated histone H3K79 hypermethylation, resulting in the activation of antioxidant responses and Wnt signaling pathway. Furthermore, HPV16 E7 knocking-out reduces LDHA nuclear translocation and H3K79 tri-methylation in K14-HPV16 transgenic mouse model. HPV16 E7 level is significantly positively correlated with nuclear LDHA and H3K79 tri-methylation in cervical cancer. Collectively, our findings uncover a non-canonical enzyme activity of nuclear LDHA to epigenetically control cellular redox balance and cell proliferation facilitating HPV-induced cervical cancer development.

Suggested Citation

  • Yuan Liu & Ji-Zheng Guo & Ying Liu & Kui Wang & Wencheng Ding & Hui Wang & Xiang Liu & Shengtao Zhou & Xiao-Chen Lu & Hong-Bin Yang & Chenyue Xu & Wei Gao & Li Zhou & Yi-Ping Wang & Weiguo Hu & Yuquan, 2018. "Nuclear lactate dehydrogenase A senses ROS to produce α-hydroxybutyrate for HPV-induced cervical tumor growth," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06841-7
    DOI: 10.1038/s41467-018-06841-7
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    Cited by:

    1. Kui Wang & Li Luo & Shuyue Fu & Mao Wang & Zihao Wang & Lixia Dong & Xingyun Wu & Lunzhi Dai & Yong Peng & Guobo Shen & Hai-Ning Chen & Edouard Collins Nice & Xiawei Wei & Canhua Huang, 2023. "PHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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