The c-MYC/NAMPT/SIRT1 feedback loop is activated in early classical and serrated route colorectal cancer and represents a therapeutic target
The c-MYC/NAMPT/SIRT1 feedback loop is activated in early classical and serrated route colorectal cancer and represents a therapeutic target
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DOI：
10.1007/s12032-018-1225-1
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发表时间：
2019-01-01
期刊：
影响因子：
3.4
通讯作者：
Menssen, Antje
中科院分区：
文献类型：
--
作者：
Brandl, Lydia;Kirstein, Nina;Menssen, Antje
我们最近发现了一个正反馈环，其中c-MYC通过转录激活烟酰胺磷酸核糖转移酶（NAMPT）和NAD（+）增加来增加沉默信息调节因子1（SIRT 1）蛋白水平和活性。在这里，我们确定了c-MYC-NAMPT-SIRT 1反馈环的相关性，包括SIRT 1抑制剂在乳腺癌1（DBC 1）中的缺失，与传统和锯齿状结直肠腺瘤的发展。对104例具有低度和高度异型增生的常规腺瘤和157例锯齿状病变的免疫组化分析显示，c-MYC、NAMPT和SIRT 1的表达升高是所有常规腺瘤和锯齿状腺瘤的特征，而DBC 1没有差异调节。分析来自43种结直肠癌细胞系的公开药物基因组学数据库表明，对NAMPT抑制剂的反应性与PTEN和TGFBR 2的改变显著相关，而BRAF或RNF 43改变或锯齿状途径结直肠癌典型的微卫星不稳定性等特征显示对NAMPT和SIRT 1抑制的敏感性增加。我们的研究结果表明，c-MYC-NAMPT-SIRT 1反馈环的激活可能对结直肠癌两种途径的启动和发展起关键作用。靶向NAMPT或SIRT 1可能代表新的治疗策略，其对锯齿状途径结肠直肠癌亚型具有更高的敏感性。
We have recently identified a positive feedback loop in which c-MYC increases silent information regulator 1 (SIRT1) protein level and activity through transcriptional activation of nicotinamide phosphoribosyltransferase (NAMPT) and NAD(+) increase. Here, we determined the relevance of the c-MYC-NAMPT-SIRT1 feedback loop, including the SIRT1 inhibitor deleted in breast cancer 1 (DBC1), for the development of conventional and serrated colorectal adenomas. Immunohistochemical analyses of 104 conventional adenomas with low- and high-grade dysplasia and of 157 serrated lesions revealed that elevated expression of c-MYC, NAMPT, and SIRT1 characterized all conventional and serrated adenomas, whereas DBC1 was not differentially regulated. Analyzing publicly available pharmacogenomic databases from 43 colorectal cancer cell lines demonstrated that responsiveness towards a NAMPT inhibitor was significantly associated with alterations in PTEN and TGFBR2, while features such as BRAF or RNF43 alterations, or microsatellite instability typical for serrated route colorectal cancer, showed increased sensitivities for inhibition of NAMPT and SIRT1. Our findings suggest an activation of the c-MYC-NAMPT-SIRT1 feedback loop that may crucially contribute to initiation and development of both routes to colorectal cancer. Targeting of NAMPT or SIRT1 may represent novel therapeutic strategies with putative higher sensitivity of the serrated route colorectal cancer subtype.