c-Myc的原癌基因需要葡萄糖摄取来驱动依赖葡萄糖的生物合成途径。为了满足这一需求，c-Myc蛋白（以下简称Myc）驱动葡萄糖转运体和糖酵解酶的表达，同时抑制与葡萄糖摄取有关的强负调节因子硫氧还蛋白相互作用蛋白（TXNIP）的表达。在三阴性乳腺癌（TNBC）中，Myc高、TXNIP低的基因特征与临床预后不良有关，而在其他乳腺癌亚型中却不具有临床意义，表明Myc和TXNIP之间存在功能关联。为了更好地了解TXNIP如何促进TNBC的侵袭行为，我们生成了TXNIP缺失的MDA-MB-231（231：TKO）细胞用于研究。我们发现，TXNIP的丧失驱动Myc类似的转录程序，并增加全局Myc基因组占据。TXNIP的丧失允许Myc侵入潜在与细胞转化有关的靶基因的启动子和增强子。这些发现表明，TXNIP是Myc基因组结合的广泛抑制因子。在231:TKO细胞中Myc基因组结合的增加扩展了我们在原始MDA-MB-231细胞中确定的Myc依赖转录组。在TXNIP丧失后，Myc依赖的转录扩展发生在没有明显增加Myc的本质转录活性和Myc水平的情况下。总之，我们的发现表明，TXNIP的丧失模拟了Myc的过度表达，将Myc基因组结合和转录程序与控制TXNIP表达的营养和增长信号联系在一起。版权所有：©Lim等人。本文是根据创作共用许可协议进行开放获取的文章，允许在任何媒介上进行无限制使用、分发和复制，前提是原作者和来源得到了相应的署名。

The c-Myc protooncogene places a demand on glucose uptake to drive glucose-dependent biosynthetic pathways. To meet this demand, c-Myc protein (Myc henceforth) drives the expression of glucose transporters, glycolytic enzymes, and represses the expression of thioredoxin interacting protein (TXNIP), which is a potent negative regulator of glucose uptake. A Mychigh/TXNIPlow gene signature is clinically significant as it correlates with poor clinical prognosis in triple-negative breast cancer (TNBC) but not in other subtypes of breast cancer, suggesting a functional relationship between Myc and TXNIP. To better understand how TXNIP contributes to the aggressive behavior of TNBC, we generated TXNIP null MDA-MB-231 (231:TKO) cells for our study. We show that TXNIP loss drives a transcriptional program that resembles those driven by Myc and increases global Myc genome occupancy. TXNIP loss allows Myc to invade the promoters and enhancers of target genes that are potentially relevant to cell transformation. Together, these findings suggest that TXNIP is a broad repressor of Myc genomic binding. The increase in Myc genomic binding in the 231:TKO cells expands the Myc-dependent transcriptome we identified in parental MDA-MB-231 cells. This expansion of Myc-dependent transcription following TXNIP loss occurs without an apparent increase in Myc's intrinsic capacity to activate transcription and without increasing Myc levels. Together, our findings suggest that TXNIP loss mimics Myc overexpression, connecting Myc genomic binding and transcriptional programs to the nutrient and progrowth signals that control TXNIP expression.Copyright: © 2023 Lim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.