Department of Oncological Sciences, Huntsman Cancer Institute, Salt Lake City, Utah, United States of America.
PLoS Biol. 2023 Mar 17;21(3):e3001778. doi: 10.1371/journal.pbio.3001778. eCollection 2023 Mar.
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.
c-Myc 原癌基因对葡萄糖摄取有需求，以驱动葡萄糖依赖性生物合成途径。为了满足这一需求，c-Myc 蛋白（简称 Myc）驱动葡萄糖转运蛋白、糖酵解酶的表达，并抑制硫氧还蛋白相互作用蛋白（TXNIP）的表达，TXNIP 是葡萄糖摄取的强有力负调控因子。Mychigh/TXNIPlow 基因特征在临床上具有重要意义，因为它与三阴性乳腺癌（TNBC）的不良临床预后相关，但与其他乳腺癌亚型无关，提示 Myc 和 TXNIP 之间存在功能关系。为了更好地了解 TXNIP 如何促进 TNBC 的侵袭行为，我们为研究生成了 TXNIP 缺失的 MDA-MB-231（231:TKO）细胞。我们表明，TXNIP 缺失驱动类似于 Myc 驱动的转录程序，并增加全局 Myc 基因组占有率。TXNIP 缺失允许 Myc 侵入目标基因的启动子和增强子，这些基因可能与细胞转化有关。总之，这些发现表明 TXNIP 是 Myc 基因组结合的广泛抑制剂。231:TKO 细胞中 Myc 基因组结合的增加扩展了我们在亲本 MDA-MB-231 细胞中鉴定的 Myc 依赖性转录组。在 TXNIP 缺失后，Myc 依赖性转录的这种扩展发生在 Myc 固有激活转录的能力没有明显增加且 Myc 水平没有增加的情况下。总之，我们的发现表明，TXNIP 缺失模拟了 Myc 过表达，将 Myc 基因组结合和转录程序与控制 TXNIP 表达的营养和促生长信号联系起来。
