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Nat Commun. 2018 Oct 24;9(1):4429. doi: 10.1038/s41467-018-06841-7.

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

Author information

1
Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P.R. China.
2
Fudan University Shanghai Cancer Center and Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, P.R. China.
3
Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai, 200032, P.R. China.
4
Department of Pathology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, P.R. China.
5
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, P.R. China.
6
Department of Pathology, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, Chengdu, 610072, P.R. China.
7
Department of Gynecology and Obstetrics, Key Laboratory of Obstetrics and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, 610041, P. R. China.
8
Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, P.R. China.
9
Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China.
10
Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P.R. China. hcanhua@scu.edu.cn.
11
Fudan University Shanghai Cancer Center and Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, P.R. China. qlei@fudan.edu.cn.
12
State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200032, P.R. China. qlei@fudan.edu.cn.

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.

PMID:
30356100
PMCID:
PMC6200739
DOI:
10.1038/s41467-018-06841-7
[Indexed for MEDLINE]
Free PMC Article

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