Lactylation-boosted polycomb repression of KLF4 elicits glycolysis in retinoblastoma: A positive feedback circuit between histone modifications

Abstract

The perturbation of histone modification homeostasis is a hallmark of oncogene activation and tumor suppressor gene silencing. Howbeit, the intricate interplay among diverse histone modifications in the context of tumorigenesis is not fully understood. Herein, we unveil a positive feedback mechanism involving lactylation and methylation of histones, which is instrumental in the oncogenic progression of retinoblastoma. First, we pinpointed that the selective upregulation of SUZ12 leads to the upregulation of H3K27me3 modification in retinoblastoma, which is attributed to heightened levels of histone lactylation. Notably, the targeted suppression of SUZ12 has demonstrated significant therapeutic benefits in both in vitro and in vivo models of retinoblastoma. Furthermore, multi-omics analysis has identified Krüppel-like factor 4 (KLF4) as a key downstream effector of SUZ12. Mechanistically, SUZ12 is implicated in the enhancement of the H3K27me3 mark on the KLF4 promoter, thereby repressing its transcription. Intriguingly, the downregulation of KLF4 is associated with an upregulation of glycolysis and a concomitant accumulation of the onco-metabolite lactate, which in turn augments histone lactylation. In conclusion, we provide novel insights into the intricate interplay between lactylation and methylation of histones, shedding light on the epigenetic-metabolic reprogramming that underlies oncogene activation and tumor suppressor gene inactivation in cancer.