He Jian, Qiu Nianxiang, Zhou Xianchao, Meng Mei, Liu Zixue, Li Jingquan, Du Shiyu, Sun Zhiqiang, Wang Hui
State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Interventional Radiology, The Tumor Hospital of Jilin Province, Changchun, China.
Front Oncol. 2023 Feb 9;12:1007653. doi: 10.3389/fonc.2022.1007653. eCollection 2022.
Resveratrol, an activator for longevity regulatory genes-sirtuin family (SIRTs) and Sirtuin 2 (SIRT2) is an important factor of SIRTs which demonstrated biological function in cancers, but the underlying mechanism is unrevealed.
We investigated the mRNA and protein levels of SIRT2 in a variety of cancers and the potential role for clinical prognosis, as well as analysed the association between the gene and immune infiltration in various cancers. And an analysis of two types of lung cancer was conducted to construct a systematic prognostic landscape. Finally, putative binding site of the triacetylresveratrol bound to SIRT2 was built from homology modeling.
We concluded that higher mRNA and protein levels of SIRT2 affected prognosis in various types of cancers, especially in LUAD cohorts. In addition, SIRT2 is linked with a better overall survival (OS) in LUAD patients. Further research suggested a possible explanation for this phenotype might be that SIRT2 mRNA levels are positively correlated with infiltrating status of multiple immunocytes in LU-AD but not LUSC, i.e. SIRT2 expression may contribute to the recruitment of CD8+T cell, CD4+ T cell, T cell CD4+ memory resting, Tregs, T cell NK and positively correlated to the expression of PD-1, also excluding neutrophil, T cell CD8+ naïve and B cell plasma cells in LUAD. We found that triacetyl-resveratrol demonstrated the most potent agonist efficiency to SIRT2 and the EC 50 as low as 142.79 nM. As a result, SIRT2 appears to be a promising novel biomarker for prognosis prediction in patients with LUAD and triacetylresveratrol might be a potential immunomodulator of LUAD to anti-PD-1 based immunotherapy combination therapies.
白藜芦醇是长寿调节基因——沉默调节蛋白家族（SIRTs）的激活剂，而沉默调节蛋白2（SIRT2）是SIRTs的一个重要因子，在癌症中具有生物学功能，但其潜在机制尚未明确。
我们研究了多种癌症中SIRT2的mRNA和蛋白水平及其对临床预后的潜在作用，并分析了该基因与各种癌症中免疫浸润的关联。对两种肺癌进行分析以构建系统的预后格局。最后，通过同源建模构建了三乙酰白藜芦醇与SIRT2的假定结合位点。
我们得出结论，SIRT2较高的mRNA和蛋白水平影响多种类型癌症的预后，尤其是在肺腺癌队列中。此外，SIRT2与肺腺癌患者更好的总生存期（OS）相关。进一步研究表明，这种表型的一个可能解释可能是SIRT2 mRNA水平与肺腺癌而非肺鳞癌中多种免疫细胞的浸润状态呈正相关，即SIRT2表达可能有助于CD8 + T细胞、CD4 + T细胞、静息CD4 +记忆T细胞、调节性T细胞、自然杀伤T细胞的募集，并且与PD - 1的表达呈正相关，在肺腺癌中也排除了中性粒细胞、幼稚CD8 + T细胞和B细胞浆细胞。我们发现三乙酰白藜芦醇对SIRT2表现出最有效的激动剂效率，半数有效浓度（EC50）低至142.79 nM。因此，SIRT2似乎是预测肺腺癌患者预后的一种有前景的新型生物标志物，三乙酰白藜芦醇可能是肺腺癌基于抗PD - 1免疫疗法联合治疗的潜在免疫调节剂。
