Lysine lactylation-based insight to understanding the characterization of cervical cancer.

ABSTRACT

Lysine lactylation (Kla), a recently discovered post-translational modification (PTM), is not only present in histone proteins but also widely distributed among non-histone proteins in tumor cells and immunocytes. However, the precise characterization and functional implications of these non-histone Kla proteins remain to be explored. Herein, a comprehensive proteomic analysis of Kla was conducted in HeLa cells. As a result, a total of 3633 Kla sites on 1637 proteins were identified. Subsequently, the stable Kla substrates were obtained and sorted to investigate the characterization and function of Kla proteins. Moreover, we characterized the Kla-related features of cervical cancers through integrative analyses of multiple datasets with proteomes, transcriptomes and single-cell transcriptome profiling. Kla-related genes (KRGs) were used to stratify cervical cancers into two clusters (C1 and C2). C2 cluster display inhibition in glycosylation and increased oxidative phosphorylation activity with high survival rate. In addition, we constructed a prognostic model based on two lactate signature genes, namely ISY1 and PPP1R14B. Interestingly, our findings revealed a negative correlation between PPP1R14B expression and the infiltration of CD8+ T cells, as well as a lower survival rate. This observation was further validated at the single-cell resolution. Simultaneously, we found that K140R mutant of PPP1R14B resulted in the decrease of Kla level and enhanced the proliferation and migration capabilities of cervical cancer cell lines, suggesting PPP1R14B-K140la has an effect on tumor behaviors. Collectively, we provides a Kla-based insight to understanding the characterization of cervical cancer, offering a potential avenue for therapeutic approaches.