P300 enhances glycolysis and dox resistance in DLBCL by upregulating HK2 expression through histone lactylation.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL), the most common lymphocytic malignancy, faces treatment challenges due to drug resistance. Glycolysis has been implicated in tumor resistance, whereas P300, an epigenetic regulator, is known to facilitate glycolysis and enhance cancer resistance. However, the underlying mechanisms linking these factors remain unreported. METHODS: Bioinformation analysis of P300 in DLBCL was conducted. P300 was overexpressed or silenced in the Doxorubicin (Dox)-sensitive or Dox-resistant DLBCL cell line, respectively. The cellular function assays were performed, and the expression of apoptosis-related and glycolysis-related proteins was detected to examine the role of P300 in the Dox resistance of DLBCL, which was further validated in vivo using xenograft models. Subsequently, rescue experiments were conducted. Chromatin immunoprecipitation (ChIP) and luciferase experiments were used to explore the underlying mechanism. ChIP was performed to measure histone lactylation levels at the Hexokinase 2 (HK2) promoter. A luciferase reporter assay was used to determine whether P300 activates hypoxia-inducible factor-1 (HIF-1) and to investigate the relationship between HIF-1 and the HK2 promoter. RESULTS: P300 expression was associated with poor prognosis of DLBCL and P300-related DEGs are mainly enriched in glycolysis, apoptosis, and other related pathways. P300 expression was higher in SU-DHL-2/ADM cells than in SU-DHL-2 cells. P300 overexpression promoted the Dox resistance of the Dox-sensitive DLBCL cell line (SU-DHL-2), while P300 silencing attenuated the Dox resistance both in vitro and in vivo. Besides, we confirmed that P300 expression facilitated glycolysis, which was associated with the Dox resistance of DLBCL. Mechanistically, P300-facilitated glycolysis induced the accumulation of lactate, which contributed to the histone lactylation on the HK2 promoter (fragment of -200 to + 1) and stimulated its transcription by interacting with HIF-1, which further bound to the HK2 promoter. CONCLUSION: Dox resistance in DLBCL was mediated by P300-facilitated glycolysis.