Role of histone acetylation in the regulation of CD36 and ANGPTL1 in esophageal squamous cell carcinoma

Given the limited efficacy of available anti-angiogenic therapies in esophageal squamous cell carcinoma (ESCC), there is a need to explore new strategies to target this crucial tumour-promoting process. Emerging evidence suggests that epigenetic dysregulation, including histone deacetylation, may contribute to aberrant pro-angiogenic signalling. Therefore, we investigated whether histone deacetylase (HDAC) 3 and HDAC8-mediated hypoacetylation contribute to the silencing of anti-angiogenic genes angiopoietin-like 1 (ANGPTL1) and cluster of differentiation (CD36), thereby promoting angiogenesis in ESCC. ESCC cell lines and clinical tissues were analysed for the expression of CD36, ANGPTL1, vascular endothelial growth factor (VEGF), HDAC3 and HDAC8 and for histone acetylation markers histone H3 lysine 9 acetylation (H3K9ac) and histone H4 lysine 16 acetylation (H4K16ac) using qRT-PCR and immunoblotting. Functional angiogenesis was assessed through in vitro human umbilical vein endothelial cell (HUVEC) tube formation, ex vivo rat aortic ring assays, and endothelial migration (wound healing/Trans well) following interventions with suberoylanilide hydroxamic acid (SAHA) treatment, HDAC3 siRNA knockdown, or CD36 overexpression. In ESCC tissues and cell lines, expression of CD36 and ANGPTL1 was downregulated, while HDAC3 and HDAC8 were upregulated, correlating with reduced levels of H3K9ac and H4K16ac. The HDAC inhibitor SAHA partially restored histone acetylation, significantly upregulated CD36 and ANGPTL1, suppressed VEGF, and reduced angiogenesis in both in vitro and ex vivo models. Furthermore, knockdown of HDAC3 produced a significant anti-angiogenic effect, comparable to the effect of CD36 overexpression. In both cases, conditioned media from the modified cells impaired endothelial cell migration and tube formation.