Lactate-mediated histone lactylation promotes melanoma angiogenesis via IL-33/ST2 axis

Abstract The pathogenesis of cancer is complicated, with metabolic reprogramming and angiogenesis as the hallmark characteristics. Recent reports have unveiled that the glycolytic metabolite lactate could modify histone lactylation to epigenetically regulate gene expressions and biological processes in cancer, while the effect on tumor angiogenesis remains elusive. By taking advantage of melanoma as the model, we first proved that lactate and histone lactylation facilitated melanoma angiogenesis both in vitro and in vivo. Then, through RNA-sequencing and a series of biochemical assays, we found that lactate promoted the transcription of suppression of tumorigenicity 2 (ST2) in tumor-associated endothelial cells via the enhancement of histone lactylation at its promoter, so that to increase the response of endothelial cells to pro-angiogenic interleukin-33 (IL-33) stimulation. In addition, lactate could also suppress high endothelial venules transition of endothelial cells, which was critical for tumor development. Ultimately, the effect of anti-angiogenic drug synergized with lactate dehydrogenase (LDH) inhibition/ST2 inhibition on melanoma growth was proved in vivo. Taken together, we demonstrated that lactate-mediated histone lactylation promotes melanoma angiogenesis via IL-33/ST2 axis, which delineated a novel regulatory relationship among lactate, histone lactylation and angiogenesis in cancer, and provided a promising combined therapeutic strategy to target angiogenesis from the perspective of cell metabolism and epigenetics in cancer.