Lactylome analyses suggest systematic lysine-lactylated substrates in oral squamous cell carcinoma under normoxia and hypoxia

Fan Song; Chen Hou; Yingzhao Huang; Jianfeng Liang; Hongshi Cai; Guoli Tian; Yaoqi Jiang; Ziyi Wang; Jinsong Hou

doi:10.1016/j.cellsig.2024.111228

Lactylome analyses suggest systematic lysine-lactylated substrates in oral squamous cell carcinoma under normoxia and hypoxia

Cell Signal. 2024 May 17:120:111228. doi: 10.1016/j.cellsig.2024.111228. Online ahead of print.

Authors

Fan Song¹, Chen Hou¹, Yingzhao Huang¹, Jianfeng Liang¹, Hongshi Cai¹, Guoli Tian¹, Yaoqi Jiang¹, Ziyi Wang¹, Jinsong Hou²

Affiliations

¹ Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China; Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China.
² Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China; Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China. Electronic address: houjs@mail.sysu.edu.cn.

PMID: 38750680
DOI: 10.1016/j.cellsig.2024.111228

Abstract

Cancer cells tend to live in hypoxic environment characterized by enhanced glycolysis and accumulation of lactate. Intracellular lactate is shown to drive a novel type of post-translational modification (PTM), lysine lactylation (Kla). Kla has been confirmed to affect the malignant progression of tumors such as hepatocellular carcinoma (HCC) and colon cancer, whereas the global lactylomic profiling of oral squamous cell carcinoma (OSCC) is unclear. Here, the integrative lactylome and proteome analyses by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified 1011 Kla sites within 532 proteins and 1197 Kla sites within 608 proteins in SCC25 cells under normoxic and hypoxic environments, respectively. Among these lactylated proteins, histones accounted for only a small fraction, suggesting the presence of Kla modification of OSCC in a large number of non-histone proteins. Notably, Kla preferred to enrich in spliceosome, ribosome and glycolysis/gluconeogenesis pathway in both normoxic and hypoxic cultures. Compared with normoxia, 589 differential proteins with 898 differentially lactylated sites were detected under hypoxia, which were mainly associated with the glycolysis/gluconeogenesis pathway by KEGG analysis. Importantly, we verified the presence of lactylation modification in the spliceosomal proteins hnRNPA1, SF3A1, hnRNPU and SLU7, as well as in glycolytic enzyme PFKP. In addition, the differential alternative splicing analysis described the divergence of pre-mRNA splicing patterns in the presence or absence of sodium lactate and at different oxygen concentrations. Finally, a negative correlation between tissue Kla levels and the prognosis of OSCC patients was revealed by immunohistochemistry. Our study is the first report to elucidate the lactylome and its biological function in OSCC, which deepens our understanding of the mechanisms underlying OSCC progression and provides a novel strategy for targeted therapy for OSCC.

Keywords: Alternative splicing; Glycolysis; Lysine lactylation; Oral squamous cell carcinoma; Post-translational modifications; Ribosome pathway.