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

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.

• Authors: 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, Qun-Ying Lei
• Journal: Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 4429 (10 24 2018) ISSN: 2041-1723 [Electronic] England
• PMID: 30356100 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hydroxybutyrates
• Isoenzymes
• Reactive Oxygen Species
• L-Lactate Dehydrogenase
• Lactate Dehydrogenase 5
• 2-hydroxybutyric acid

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation (genetics, physiology)
• Chromatin Immunoprecipitation
• Female
• Fluorescent Antibody Technique
• Hydroxybutyrates (metabolism)
• Isoenzymes (genetics, metabolism)
• L-Lactate Dehydrogenase (genetics, metabolism)
• Lactate Dehydrogenase 5
• Male
• Mice
• Mice, Nude
• Papillomavirus Infections (complications, metabolism)
• Reactive Oxygen Species (metabolism)
• Tandem Mass Spectrometry
• Uterine Cervical Neoplasms (etiology, metabolism)
• Wnt Signaling Pathway (genetics, physiology)
• Xenograft Model Antitumor Assays