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

• Published in: Nature communications Vol. 9; no. 1; pp. 4429 - 16
• Main Authors: Liu, Yuan, Guo, Ji-Zheng, Liu, Ying, Wang, Kui, Ding, Wencheng, Wang, Hui, Liu, Xiang, Zhou, Shengtao, Lu, Xiao-Chen, Yang, Hong-Bin, Xu, Chenyue, Gao, Wei, Zhou, Li, Wang, Yi-Ping, Hu, Weiguo, Wei, Yuquan, Huang, Canhua, Lei, Qun-Ying
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.10.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/109; 13/51; 13/89; 14/63; 38/15; 38/88; 631/67/1517/1371; 631/67/2327; 64/60; 82/58; Animals; Antioxidants; Cancer; Carcinogenesis; Carcinogens; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Cell Proliferation - physiology; Cervical cancer; Cervix; Chromatin Immunoprecipitation; Dehydrogenase; Dehydrogenases; Enzymatic activity; Enzyme activity; Enzymes; Female; Fluorescent Antibody Technique; Human papillomavirus; Humanities and Social Sciences; Hydroxybutyrates - metabolism; Initiators; Isoenzymes - genetics; Isoenzymes - metabolism; L-Lactate dehydrogenase; L-Lactate Dehydrogenase - genetics; L-Lactate Dehydrogenase - metabolism; Lactate dehydrogenase; Lactic acid; Male; Methylation; Mice; Mice, Nude; multidisciplinary; Nuclear transport; Papillomavirus Infections - complications; Papillomavirus Infections - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; Rodents; Science; Science (multidisciplinary); Signal transduction; Tandem Mass Spectrometry; Transgenic mice; Translocation; Tumors; Uterine Cervical Neoplasms - etiology; Uterine Cervical Neoplasms - metabolism; Viruses; Wnt protein; Wnt Signaling Pathway - genetics; Wnt Signaling Pathway - physiology; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-06841-7

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. High-risk human papilloma virus (HR-HPV) infection is strongly associated with cervical cancer and current evidences link E7 to HPV-associated carcinogenesis. Here the authors propose a model in which the infection of epithelial cells with high risk HPV results in a burst of reactive oxygen species, translocation of LDHA to the nucleus and activation of a gene profile that supports the growth of cervical cancer.