Inhibition of SIRT2 limits tumour angiogenesis via inactivation of the STAT3/VEGFA signalling pathway

摘要

Mounting evidence has demonstrated that angiogenesis plays an important role in tumour progression. However, the key regulators in tumour angiogenesis remain unclear. Recently, emerging reports have indicated that SIRT2 plays critical roles in proliferation, metastasis and tumourigenesis in diverse tumours. However, the function of SIRT2 in tumour angiogenesis and the mechanism underlying the regulation of angiogenesis by SIRT2 are still unknown. Here, we found that SIRT2 was upregulated in colorectal cancer tissues compared to that in normal samples and that the elevated SIRT2 was associated with poor prognosis in patients with colorectal cancer. In addition, a series of in vitro and in vivo experiments were performed to demonstrate the role of SIRT2 in tumour angiogenesis. We showed that silencing SIRT2 significantly suppressed tumour angiogenesis. Mechanistically, the knockdown of SIRT2 inhibited STAT3 phosphorylation, causing decreased secretion of VEGFA. Notably, we found that SIRT2 directly interacted with STAT3 and affected the phosphorylation of STAT3 and the translocation of phosphorylated STAT3 to the nucleus. Importantly, a series of rescue experiments suggested that the function of SIRT2 in tumour angiogenesis depends on the STAT3/VEGFA signalling pathway. Our findings provide insight into the important role of SIRT2 in colon tumour angiogenesis and suggest that SIRT2/STAT3/VEGFA might be a novel prognostic biomarker and a potential therapeutic target for patients with colorectal cancer.