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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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Liu Y,Guo JZ,Liu Y,Wang K,Ding W,Wang H,Liu X,Zhou S,Lu XC,Yang HB,Xu C,Gao W,Zhou L,Wang YP,Hu W,Wei Y,Huang C,Lei QY

doi

10.1038/s41467-018-06841-7

subject

Has Abstract

pub_date

2018-10-24 00:00:00

pages

4429

issue

1

issn

2041-1723

pii

10.1038/s41467-018-06841-7

journal_volume

9

pub_type

杂志文章

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