Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
Division of Colon and Rectal Surgery, Department of Surgery, Gil Medical Center, Gachon University College of Medicine, Incheon, 21565, Republic of Korea.
Cancer Lett. 2018 Sep 1;431:219-229. doi: 10.1016/j.canlet.2018.05.036. Epub 2018 May 26.
SIRT1, an NAD-dependent histone/protein deacetylase, has diverse physiological actions. Recent studies have demonstrated that SIRT1 is overexpressed in colorectal cancer, suggesting its oncogenic potential. However, the molecular mechanisms by which overexpressed SIRT1 induces the progression of colorectal cancer and its inhibition remain largely unknown. Curcumin (diferuloymethane), a major component of the spice turmeric derived from the plant Curcuma longa L., has been reported to exert chemopreventive and anti-carcinogenic effects on colon carcinogenesis. In the present study, we found that curcumin reduced the expression of SIRT1 protein without influencing its mRNA expression in human colon cancer cells, suggesting posttranslational regulation of SIRT1 by this phytochemical. Notably, ubiquitination and subsequent proteasomal degradation of SIRT1 were induced by curcumin treatment. Results of nano-LC-ESI-MS/MS revealed the direct binding of curcumin to cysteine 67 of SIRT1. In line with this result, the protein stability and clonogenicity of a mutant SIRT1 in which cysteine 67 was substituted by alanine were unaffected by curcumin. Taken together, these observations suggest that curcumin facilitates the proteasomal degradation of oncogenic SIRT1 through covalent modification of SIRT1 at the cysteine 67 residue.
SIRT1 是一种 NAD 依赖性组蛋白/蛋白去乙酰化酶，具有多种生理作用。最近的研究表明，SIRT1 在结直肠癌中过度表达，提示其致癌潜能。然而，过度表达的 SIRT1 诱导结直肠癌进展及其抑制的分子机制在很大程度上仍不清楚。姜黄素（二芳基甲酮）是来自植物姜黄的香料 turmeric 的主要成分，据报道对结肠癌发生具有化学预防和抗癌作用。在本研究中，我们发现姜黄素降低了人结肠癌细胞中 SIRT1 蛋白的表达，而不影响其 mRNA 表达，提示这种植物化学物质对 SIRT1 进行翻译后调节。值得注意的是，姜黄素处理诱导了 SIRT1 的泛素化和随后的蛋白酶体降解。纳升 LC-ESI-MS/MS 的结果表明姜黄素直接与 SIRT1 的半胱氨酸 67 结合。与该结果一致，用姜黄素处理时，突变 SIRT1（其中半胱氨酸 67 被丙氨酸取代）的蛋白稳定性和集落形成能力不受影响。综上所述，这些观察结果表明，姜黄素通过 SIRT1 半胱氨酸 67 残基的共价修饰促进致癌 SIRT1 的蛋白酶体降解。
