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

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 Wei, Canhua Huang () and Qun-Ying Lei ()
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Yuan Liu: Sichuan University, and Collaborative Innovation Center for Biotherapy
Ji-Zheng Guo: 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

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06841-7

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