The SIRT2/cMYC Pathway Inhibit Peroxidation-Related Apoptosis In Cholangiocarcinoma Through Metabolic Reprogramming
The SIRT2/cMYC Pathway Inhibit Peroxidation-Related Apoptosis In Cholangiocarcinoma Through Metabolic Reprogramming
复制标题
SIRT2/cMYC 通路通过代谢重编程抑制胆管癌中过氧化相关的细胞凋亡
DOI：
10.1016/j.neo.2019.03.002
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发表时间：
2019-05-01
期刊：
影响因子：
4.8
通讯作者：
Zhang, Mingming
中科院分区：
文献类型：
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作者：
Xu, Lei;Wang, Lei;Zhang, Mingming
胆管癌（CCA）是一种病因不明、预后不良的恶性肿瘤。大多数患者在诊断时已处于晚期，因此寻找新的 CCA 治疗靶点至关重要。肿瘤细胞的代谢重编程包括葡萄糖（称为瓦伯格效应）和其他物质（例如氨基酸和脂肪）的代谢异常。代谢重编程产生抗氧化物质，降低肿瘤氧化应激，最终促进肿瘤增殖。越来越多的证据表明 SIRT2（一种组蛋白脱乙酰酶）及其下游靶标 cMYC 在肿瘤细胞中发挥代谢调节作用。然而，SIRT2/cMYC 通路在 CCA 中的作用尚不清楚。为了评估SIRT2/cMYC通路在CCA中的代谢重编程功能并确定下游靶点以及评估治疗效果，从TCGA数据库下载CCA RNA-Seq数据。确认差异表达基因并进行KEGG通路富集分析。总体而言，收集了48对配对的CCA样本并进行免疫组织化学检测，并总结了参与者的临床特征。 CCA细胞被SIRT2的不同下游靶点抑制或过表达，然后进行细胞凋亡、免疫印迹、海马和代谢物追踪分析。还进行了体内实验。我们发现SIRT2/cMYC通路有助于CCA细胞的增殖，并证实下游靶点是PHDA1和丝氨酸合成通路。 SIRT2 和 cMYC 水平上调导致线粒体氧化磷酸化水平降低，葡萄糖向丝氨酸的转化增加，导致患者生存率下降。高活性的 SIRT2/cMYC 通路上调丝氨酸合成通路丙酮酸并增加抗氧化剂的产生，从而保护 CCA 细胞免受氧化应激诱导的细胞凋亡。我们的数据显示，SIRT2/cMYC 通路在将葡萄糖氧化代谢转化为丝氨酸合成代谢代谢中发挥着关键作用，从而为抗应激提供抗氧化剂。 SIRT2/cMYC 诱导的代谢重编程可能代表治疗 CCA 的新治疗靶点。
Cholangiocarcinoma (CCA) is a malignant cancer with an unknown etiology and an unfavorable prognosis. Most patients are diagnosed at an advanced stage, thus making it essential to find novel curative targets for CCA. Metabolic reprogramming of the tumor cells includes metabolic abnormalities in glucose (known as the Warburg effect) and other substances such as amino acids and fats. Metabolic reprogramming produces anti-oxidant substances, reduces tumor oxidative stress, and finally promotes the proliferation of tumors. There is increasing evidence to imply that SIRT2, a histone deacetylase, and its downstream target cMYC, play metabolic regulatory roles in tumor cells. However, the role of the SIRT2/cMYC pathway in CCA is unclear. To assess the metabolic reprogramming function of the SIRT2/cMYC pathway in CCA and to determine the downstream targets as well as evaluate the therapeutic effect, the CCA RNA-Seq data were downloaded from the TCGA database. Differentially expressed genes were confirmed and KEGG pathway enrichment analysis was performed. Overall, 48 paired CCA samples were collected and subjected to immunohistochemical detection, and the clinical characteristics of participants were summarized. The CCA cells were suppressed or overexpressed with different downstream targets of SIRT2 and then subjected to apoptosis, immunoblotting, seahorse, and metabolites tracing analysis. In vivo experiments were also performed. We found that the SIRT2/cMYC pathway contributed to the proliferation of CCA cells and confirmed that the downstream target is PHDA1 and the serine synthesis pathway. The up-regulated SIRT2 and cMYC levels resulted in low levels of mitochondrial oxidative phosphorylation and increased conversion of glucose to serine and led to poor patient survival. The highly active SIRT2/cMYC pathway upregulated the serine synthesis pathway pyruvate and increased antioxidant production, thus consequently protecting the CCA cells from oxidative stress-induced apoptosis. Our data revealed that the SIRT2/cMYC pathway plays a critical role in transforming glucose oxidative metabolism to serine anabolic metabolism, thus providing antioxidants for stress resistance. SIRT2/cMYC-induced metabolic reprogramming may represent a new therapeutic target for treating CCA.