Nuclear lactate dehydrogenase A senses ROS to produce α-hydroxybutyrate for HPV-induced cervical tumor growth
Nuclear lactate dehydrogenase A senses ROS to produce α-hydroxybutyrate for HPV-induced cervical tumor growth
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核乳酸脱氢酶 A 感应 ROS 产生 α-羟基丁酸，促进 HPV 诱导的宫颈肿瘤生长。
DOI：
10.1038/s41467-018-06841-7
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发表时间：
2018-10-24
影响因子：
16.6
通讯作者：
Lei, Qun-Ying
中科院分区：
文献类型：
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作者：
Liu, Yuan;Guo, Ji-Zheng;Lei, Qun-Ying
众所周知，高危人乳头瘤病毒（HR-HPV）感染与宫颈癌密切相关，而E7被确定为HPV介导的癌变的关键启动子之一。在这里，我们发现，由于 E7 诱导细胞内活性氧 (ROS) 积累，乳酸脱氢酶 A (LDHA) 优选位于 HPV16 阳性宫颈肿瘤的细胞核中。令人惊讶的是，细胞核 LDHA 获得了非典型酶活性，可产生 α-羟基丁酸，并触发 DOT1L（端粒沉默干扰素 1 样）介导的组蛋白 H3K79 高甲基化，从而激活抗氧化反应和 Wnt 信号通路。此外，在 K14-HPV16 转基因小鼠模型中，HPV16 E7 敲除可减少 LDHA 核易位和 H3K79 三甲基化。宫颈癌中HPV16 E7水平与核LDHA和H3K79三甲基化显着正相关。总的来说，我们的研究结果揭示了核 LDHA 的非典型酶活性，可通过表观遗传控制细胞氧化还原平衡和细胞增殖，从而促进 HPV 诱导的宫颈癌的发展。
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.