Metabolic reprogramming in triple-negative breast cancer through Myc suppression of TXNIP
Metabolic reprogramming in triple-negative breast cancer through Myc suppression of TXNIP
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DOI：
10.1073/pnas.1501555112
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发表时间：
2015-04-28
影响因子：
11.1
通讯作者：
Ayer, Donald E.
中科院分区：
文献类型：
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作者：
Shen, Liangliang;O'Shea, John M.;Ayer, Donald E.
三阴性乳腺癌（TNBC）是侵袭性的，缺乏靶向治疗。了解营养素在TNBC中的使用方式可能为治疗干预提供新的靶点。我们证明，转录因子c-Myc驱动TNBC细胞中的葡萄糖代谢，但这样做的一个以前不受重视的机制，涉及直接抑制硫氧还蛋白相互作用蛋白（TXNIP）。TXNIP是葡萄糖摄取、有氧糖酵解和糖酵解基因表达的有效负调节剂;因此其被c-Myc抑制提供了c-Myc驱动的葡萄糖代谢的替代途径。c-Myc通过与TXNIP启动子中的含E-box区域结合来降低TXNIP基因表达，可能与相关转录因子MondoA竞争。TXNIP抑制增加葡萄糖摄取并驱动对糖酵解的依赖。异位TXNIP表达降低葡萄糖摄取，减少细胞增殖，并增加凋亡。支持c-Myc和TXNIP之间相互关系的生物学意义，Myc（高）/TXNIP低基因标记与乳腺癌中总生存率降低和无转移生存率降低相关。Myc（高）/TXNIPlow基因签名与不良临床结果之间的相关性仅在TNBC中是明显的，而在其他乳腺癌亚类中不是。TP 53的突变是TNBC的定义性分子特征，其增强了Myc（高）/TXNIPlow基因签名与乳腺癌死亡之间的相关性。由于Myc驱动养分利用和TXNIP限制葡萄糖的可用性，我们建议Myc（高）/TXNIP低基因签名协调养分利用与养分可用性。此外，我们的数据表明，p53肿瘤抑制因子的缺失与Myc（高）/TXNIP低驱动的代谢失调合作，以驱动TNBC的侵袭性临床行为。
Triple-negative breast cancers (TNBCs) are aggressive and lack targeted therapies. Understanding how nutrients are used in TNBCs may provide new targets for therapeutic intervention. We demonstrate that the transcription factor c-Myc drives glucose metabolism in TNBC cells but does so by a previously unappreciated mechanism that involves direct repression of thioredoxin-interacting protein (TXNIP). TXNIP is a potent negative regulator of glucose uptake, aerobic glycolysis, and glycolytic gene expression; thus its repression by c-Myc provides an alternate route to c-Myc-driven glucose metabolism. c-Myc reduces TXNIP gene expression by binding to an E-box-containing region in the TXNIP promoter, possibly competing with the related transcription factor MondoA. TXNIP suppression increases glucose uptake and drives a dependence on glycolysis. Ectopic TXNIP expression decreases glucose uptake, reduces cell proliferation, and increases apoptosis. Supporting the biological significance of the reciprocal relationship between c-Myc and TXNIP, a Myc(high)/TXNIPlow gene signature correlates with decreased overall survival and decreased metastasis-free survival in breast cancer. The correlation between the Myc(high)/TXNIPlow gene signature and poor clinical outcome is evident only in TNBC, not in other breast cancer subclasses. Mutation of TP53, which is a defining molecular feature of TNBC, enhances the correlation between the Myc(high)/TXNIPlow gene signature and death from breast cancer. Because Myc drives nutrient utilization and TXNIP restricts glucose availability, we propose that the Myc(high)/TXNIPlow gene signature coordinates nutrient utilization with nutrient availability. Further, our data suggest that loss of the p53 tumor suppressor cooperates with Myc(high)/TXNIPlow-driven metabolic dysregulation to drive the aggressive clinical behavior of TNBC.