Lactylation-driven KRT19 promotes non-small cell lung cancer progression by suppressing cellular senescence

Abstract Background Cellular senescence provides a protective barrier against tumorigenesis. However, the detailed mechanisms underlying tumor cells bypass senescence to malignant progression of non-small cell lung cancer (NSCLC) are still poorly understood. Methods In this study, we assessed the impact of KRT19 on NSCLC using xenograft tumor models, EdU, CCK8, colony formation and transwell assay. We performed chromatin immunoprecipitation sequencing and dual luciferase reporter assay to explore the mechanism through which H3K18 lactylation (H3K18la) mediated KRT19. The mechanism underlying KRT19 regulated p21-driven cellular senescence was explored by senescence-associated β-galactosidase staining, flow cytometry and further identified by RNA sequencing, mass spectrometry, immunofluorescence, co-immunoprecipitation and protein ubiquitination assay. The clinical significance of H3K18la/KRT19/p21 was determined by immunohistochemistry in human NSCLC specimens and bioinformatics analysis of TCGA database and Kaplan-Meier method. We evaluated the effects of KRT19 inhibition and anti-PD-1 on NSCLC growth and immune infiltration using xenograft tumor models, flow cytometry and CIBERSORT. Results Our study revealed that elevated expression of KRT19 was correlated with poor prognosis of NSCLC patients and exhibited oncogenic activity in NSCLC. Mechanistically, lactate-derived H3K18la activated the transcription of KRT19 via directly binding to its promoter. KRT19 blocked the transcriptional activation of p21 by p53, alternatively, KRT19 also interacted with MYH9 to facilitate ubiquitination of p21 at K16. More significantly, blockade of KRT19 potently enhanced the cytotoxic function of tumor-infiltrating CD8 + T cells and synergistically repressed NSCLC progression when combining with anti-PD-1. Conclusion Our study emphasizes the importance of lactylation-driven KRT19 for overriding senescence and promoting NSCLC progression, reinforcing the potential of combination therapy strategies with KRT19 inhibitors to yield favorable responses in patients with NSCLC. Graphical abstract Lactate-derived H3K18 lactylation increases the expression of KRT19, which overrides p21-driven cellular senescence to promote NSCLC progression through inhibiting the transcriptional activation of p21 by p53 and facilitating MYH9-mediated ubiquitination of p21 at K16. Silencing of KRT19 potently induces senescence program in NSCLC cells and boosts anti-PD-1 immunotherapy efficiency by potentiating stronger antineoplastic responses of tumor-infiltrating cytotoxic CD8 + T cells. Graphical abstract