Sirtuin 2（SIRT2）和组蛋白 H3K18 乙酰化途径的失调与不良的前列腺癌结局相关。
Dysregulation of Sirtuin 2 (SIRT2) and histone H3K18 acetylation pathways associates with adverse prostate cancer outcomes.
机构信息
Department of Urology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53705, USA.
Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA.
出版信息
BMC Cancer. 2017 Dec 20;17(1):874. doi: 10.1186/s12885-017-3853-9.
BACKGROUND
Histones undergo extensive post-translational modifications and this epigenetic regulation plays an important role in modulating transcriptional programs capable of driving cancer progression. Acetylation of histone H3K18, associated with gene activation, is enhanced by P300 and opposed by the deacetylase Sirtuin2 (SIRT2). As these enzymes represent an important target for cancer therapy, we sought to determine whether the underlying genes are altered during prostate cancer (PCa) progression.
METHODS
Tissue microarrays generated from 71 radical prostatectomy patients were initially immunostained for H3K18Ac, P300 and SIRT2. Protein levels were quantified using VECTRA automation and correlated with clinicopathologic parameters. The Cancer Genome Atlas (TGCA, n = 499) and Gene Expression Omnibus (n = 504) databases were queried for expression, genomic and clinical data. Statistics were performed using SPSSv23.
RESULTS
Nuclear histone H3K18Ac staining increases in primary cancer (p = 0.05) and further in metastases (p < 0.01) compared to benign on tissue arrays. P300 protein expression increases in cancer (p = 0.04) and metastases (p < 0.001). A progressive decrease in nuclear SIRT2 staining occurs comparing benign to cancer or metastases (p = 0.04 and p = 0.03 respectively). Decreased SIRT2 correlates with higher grade cancer (p = 0.02). Time to Prostate Specific Antigen (PSA) recurrence is shorter in patients exhibiting high compared to low H3K18Ac expression (350 vs. 1542 days respectively, P = 0.03). In GEO, SIRT2 mRNA levels are lower in primary and metastatic tumors (p = 0.01 and 0.001, respectively). TGCA analysis demonstrates SIRT2 deletion in 6% and increasing clinical stage, positive margins and lower PSA recurrence-free survival in patients with SIRT2 loss/deletion (p = 0.01, 0.04 and 0.04 respectively). In this dataset, a correlation between decreasing SIRT2 and increasing P300 mRNA expression occurs in tumor samples (R = -0.46).
CONCLUSIONS
In multiple datasets, decreases in SIRT2 expression portend worse clinicopathologic outcomes. Alterations in SIRT2-H3K18Ac suggest altered P300 activity and identify a subset of tumors that could benefit from histone deacetylation inhibition.
背景
组蛋白经历广泛的翻译后修饰，这种表观遗传调控在调节能够驱动癌症进展的转录程序中起着重要作用。与基因激活相关的组蛋白 H3K18 的乙酰化由 P300 增强，而由去乙酰化酶 Sirtuin2（SIRT2）拮抗。由于这些酶是癌症治疗的重要靶点，我们试图确定在前列腺癌（PCa）进展过程中是否改变了潜在基因。
方法
从 71 例根治性前列腺切除术患者中生成组织微阵列，最初用 H3K18Ac、P300 和 SIRT2 进行免疫染色。使用 VECTRA 自动化定量蛋白质水平，并将其与临床病理参数相关联。查询癌症基因组图谱（TCGA，n=499）和基因表达综合数据库（n=504）以获取表达、基因组和临床数据。使用 SPSSv23 进行统计分析。
结果
与良性相比，组织阵列中的原发性癌症（p=0.05）和转移灶中核组蛋白 H3K18Ac 染色增加（p<0.01）。癌组织（p=0.04）和转移灶（p<0.001）中 P300 蛋白表达增加。与良性相比，核 SIRT2 染色逐渐减少，分别为癌症（p=0.04）和转移灶（p=0.03）。SIRT2 减少与癌症分级较高相关（p=0.02）。与低 H3K18Ac 表达相比，高 H3K18Ac 表达的患者的前列腺特异性抗原（PSA）复发时间更短（分别为 350 天和 1542 天，P=0.03）。在 GEO 中，SIRT2 mRNA 水平在原发性和转移性肿瘤中均较低（p=0.01 和 0.001）。TCGA 分析表明，在 SIRT2 缺失的患者中，6%存在 SIRT2 缺失，并且在临床分期、阳性切缘和 PSA 无复发生存率降低（p=0.01、0.04 和 0.04）方面存在 SIRT2 缺失/缺失。在该数据集，在肿瘤样本中观察到 SIRT2 表达减少与 P300 mRNA 表达增加之间存在相关性（R=-0.46）。
结论
在多个数据集，SIRT2 表达减少预示着更差的临床病理结局。SIRT2-H3K18Ac 的改变表明 P300 活性改变，并确定了可能受益于组蛋白去乙酰化抑制的肿瘤亚群。
Zotero 插件