Histone lactylation-driven feedback loop modulates pyrimidine metabolism to promote oral carcinogenesis
Cell Death and Disease, vol. 17
Abstract
Metabolic reprogramming and epigenetic alterations promote oral squamous cell carcinoma (OSCC). Lactate-dependent histone modification is a novel histone mark that connects the epigenetic process of lactylation to glycolytic metabolites. However, the role of histone lactylation in oral carcinogenesis remains poorly understood. In this study, the levels of histone lactylation in oral leukoplakia (OLK) and OSCC tissues were determined by immunohistochemistry. The involvement of histone lactylation in OSCC initiation was assessed by the inhibition of lactylation using glycolysis inhibitors or silencing lactate dehydrogenase A (LDHA), both in vitro and in vivo. CUT&Tag, scRNA-seq, ChIP-qPCR, and rescue experiments were conducted to explore the potential molecular mechanism of H3K18 lactylation (H3K18la) in OSCC tumorigenesis. Histone lactylation, particularly H3K18la levels were elevated in OLK and OSCC tissues. The inhibition of histone lactylation repressed the malignant phenotypes of OLK and OSCC cells in vitro. Glycolysis inhibitors blocked the formation of precancerous lesions and OSCC in the 4NQO-induced tongue carcinogenesis model. Mechanistically, H3K18la activated the transcription of thymidine kinase 1 (TK1) and increased TK1-mediated pyrimidine biosynthesis, resulting in oral carcinogenesis. TK1 downregulation inhibited the Wnt signaling pathway via RhoA. Moreover, the Wnt/β-catenin inhibitor XAV939 reduced lactate production and H3K18la levels. Here, we demonstrate that the glycolysis/H3K18la/TK1/β-catenin positive feedback loop exacerbates dysfunction in OSCC initiation. These findings reveal a novel link between epigenetic regulation and lactate-driven metabolic reprogramming, which may lead to the development of innovative lactylation treatment approaches for OSCC therapy.
Authors 9
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Yanting Wang corresponding
Affiliation as printed
Department of Oral Mucosal Diseases, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China. wyt@njmu.edu.cn
Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China. wyt@njmu.edu.cn
State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing, China. wyt@njmu.edu.cn
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Affiliation as printed
Department of Oral Mucosal Diseases, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing, China
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Affiliation as printed
Stomatological College of Nanjing Medical University, Nanjing, China
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Affiliation as printed
Stomatological College of Nanjing Medical University, Nanjing, China
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Affiliation as printed
Stomatological College of Nanjing Medical University, Nanjing, China
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Affiliation as printed
Stomatological College of Nanjing Medical University, Nanjing, China
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Leiden University Medical Center
Affiliation as printed
Department of Oral and Maxillofacial Surgery, Leiden University Medical Center (LUMC), Leiden, the Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Oral and Maxillofacial Surgery, Leiden University Medical Center (LUMC), Leiden, the Netherlands
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Y Fan corresponding
Affiliation as printed
Department of Oral Mucosal Diseases, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China. fanyuan@njmu.edu.cn
Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China. fanyuan@njmu.edu.cn
State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing, China. fanyuan@njmu.edu.cn
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