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.

Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8 + T cell stemness and antitumor immunity

“…4E, blue arrows). Although the basis for the transcriptomic changes is not known, nuclear LDHA can affect H3K79 methylation (34), and histone lactylation might also contribute (35), an area for further investigation. These phenotypic and transcriptomic data suggest that LDHi might be capable of enhancing the antitumor activity of CD8 + T cells.…”

Metabolite sensing and signaling in cancer

“…Nuclear LDHA produces a-hydroxybutyrate (a-HB) and epigenetically activates Wnt signaling by enhancing disruptor of telomeric silencing 1-like (DOT1L)mediated histone H3 Lys-79 methylation. a-HB-DOT1L-Wnt signaling is critical in maintaining redox balance in human papillomavirus-induced cervical cancer (30). a-HB signaling potentially cooperates with Wnt/b-catenin signals to promote cell proliferation in several types of cancer.…”

An Integrated Meta-Analysis of Secretome and Proteome Identify Potential Biomarkers of Pancreatic Ductal Adenocarcinoma

“…Moreover, LDHA has been reported to improve growth and inhibit apoptosis in pancreatic tumor cells [138]. Mohammad et al [139] showed that increased expression of LDHA and PKM2 in pancreatic biopsy specimens from patients correlates with poor survival. Studies investigating the LDH expression levels in tumor and serum found that high tissue expression is not entirely consistent with elevated serum levels, indicating that tumor LDHA expression and serum levels are two independent predictors of the disease [140].…”