H3K18 lactylation promotes POM121 transcription and accelerates gastric cancer progression via the PI3K/AKT pathway

Gastric cancer (GC) is a common and lethal malignancy of the digestive system. Histone lactylation, a modification linked to metabolic stress, plays a critical role in tumor initiation and progression. However, the specific contribution of histone lactylation, particularly at the H3K18 site (H3K18la), to GC progression remains poorly understood.

Twenty paired GC and adjacent non-cancerous tissue samples were collected. The expression levels of pan lactylation (Kla) and H3K18la were detected in GC tissues and cells by Western blot. LDHA and LDHB were silenced to reduce H3K18la levels in GC cells. Cell proliferation, migration, invasion, and apoptosis were assessed using CCK-8, colony formation, wound healing, Transwell, and flow cytometry assays. Xenograft tumor models (n = 6 per group) were established to evaluate in vivo tumor growth. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were performed to investigate the regulatory mechanism of H3K18la on POM121 transcription. KEGG pathway analysis and rescue experiments were conducted to explore downstream signaling pathways.

Elevated levels of Kla and H3K18la were observed in GC tissues and cells. Decreased expression of H3K18la by silencing LDHA and LDHB suppressed cell proliferation and metastasis while promoting apoptosis both in vitro and in vivo. Mechanistically, H3K18la enrichment at the POM121 promoter region was associated with enhanced transcription. POM121 overexpression reversed the inhibitory effects of H3K18la reduction on GC cell malignant behaviors. Furthermore, POM121 activated the PI3K/AKT signaling pathway, and inhibition of this pathway by LY294002 attenuated the oncogenic effects of POM121 overexpression.

H3K18la enhances the malignant behavior of GC cells through activation of the POM121/PI3K/AKT pathway. These findings provide new insights into the role of histone lactylation in GC progression and suggest that targeting the H3K18la-POM121-PI3K/AKT axis may represent a potential therapeutic avenue worthy of further investigation.