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 alpha-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.
基金：
MOST [2015CB910401]; NSFC [81790253, 81790251, 81821002, 81430057, 81430071, 81672381]; Sichuan Science and Technology Program [2018RZ0133]; Shanghai Municipal Education Commission [N173606]
第一作者单位：[1]Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Dept Biotherapy, Chengdu 610041, Sichuan, Peoples R China[2]Sichuan Univ, West China Hosp, Canc Ctr, Chengdu 610041, Sichuan, Peoples R China[3]Sichuan Univ, West China Sch Basic Med Sci & Forens Med, Chengdu 610041, Sichuan, Peoples R China
通讯作者：
通讯机构：[1]Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Dept Biotherapy, Chengdu 610041, Sichuan, Peoples R China[2]Sichuan Univ, West China Hosp, Canc Ctr, Chengdu 610041, Sichuan, Peoples R China[3]Sichuan Univ, West China Sch Basic Med Sci & Forens Med, Chengdu 610041, Sichuan, Peoples R China[4]Fudan Univ, Shanghai Canc Ctr, Shanghai 200032, Peoples R China[5]Fudan Univ, Shanghai Med Coll, Inst Biomed Sci, Canc Metab Lab, Shanghai 200032, Peoples R China[14]Fudan Univ, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China
推荐引用方式(GB/T 7714)：
Liu Yuan,Guo Ji-Zheng,Liu Ying,et al.Nuclear lactate dehydrogenase A senses ROS to produce α-hydroxybutyrate for HPV-induced cervical tumor growth[J].NATURE COMMUNICATIONS.2018,9:doi:10.1038/s41467-018-06841-7.
APA：
Liu, Yuan,Guo, Ji-Zheng,Liu, Ying,Wang, Kui,Ding, Wencheng...&Lei, Qun-Ying.(2018).Nuclear lactate dehydrogenase A senses ROS to produce α-hydroxybutyrate for HPV-induced cervical tumor growth.NATURE COMMUNICATIONS,9,
MLA：
Liu, Yuan,et al."Nuclear lactate dehydrogenase A senses ROS to produce α-hydroxybutyrate for HPV-induced cervical tumor growth".NATURE COMMUNICATIONS 9.(2018)
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