SIRT2 is required for NaBT-induced CRC cell differentiation

Activation of the Wnt/β-catenin pathway is one of the hallmarks of colorectal cancer (CRC). Sirtuin 2 (SIRT2) protein has been shown to inhibit CRC proliferation. Previously, we reported that SIRT2 plays an important role in the maintenance of normal intestinal cell homeostasis. Here, we show that SIRT2 is a direct target gene of Wnt/β-catenin signaling in CRC cells. Inhibition or knockdown of Wnt/β-catenin increased SIRT2 promoter activity and mRNA and protein expression, whereas activation of Wnt/β-catenin decreased SIRT2 promoter activity and expression. β-catenin was recruited to the promoter of SIRT2 and transcriptionally regulated SIRT2 expression. Wnt/β-catenin inhibition increased mitochondrial oxidative phosphorylation (OXPHOS) and CRC cell differentiation. Moreover, inhibition of OXPHOS attenuated the differentiation of CRC cells induced by Wnt/β-catenin inhibition. In contrast, inhibition or knockdown of SIRT2 decreased, while overexpression of SIRT2 increased, OXPHOS activit..., ,

Wnt/β-连环蛋白（Wnt/β-catenin）通路的激活是结直肠癌（colorectal cancer, CRC）的标志性特征之一。沉默信息调节因子2（Sirtuin 2, SIRT2）已被证实可抑制结直肠癌细胞的增殖。本团队此前的研究表明，SIRT2在维持正常肠道细胞稳态过程中发挥关键作用。本研究证实，SIRT2是结直肠癌细胞中Wnt/β-连环蛋白信号通路的直接靶基因。抑制或敲低Wnt/β-连环蛋白通路可增强SIRT2启动子活性及其mRNA与蛋白表达水平，而激活该通路则会降低SIRT2的启动子活性与表达。β-连环蛋白可被招募至SIRT2的启动子区域，并对SIRT2的表达进行转录调控。抑制Wnt/β-连环蛋白通路可提升线粒体氧化磷酸化（mitochondrial oxidative phosphorylation, OXPHOS）水平，并促进结直肠癌细胞分化。此外，抑制OXPHOS可削弱Wnt/β-连环蛋白通路抑制所诱导的结直肠癌细胞分化。与之相反，抑制或敲低SIRT2会降低OXPHOS活性，而过表达SIRT2则会提升OXPHOS活性……