MUC1-C 蛋白的激活可促进谱系可塑性、表观遗传重编程和癌症干细胞 (CSC) 状态。目前对三阴性乳腺癌 (TNBC) CSC 富集群体进行的研究表明，MUC1-C 对于整合糖酵解途径基因的激活与自我更新和致瘤性至关重要。 MUC1-C 进一步将糖酵解途径与编码线粒体复合物 I-V 成分的线粒体 DNA (mtDNA) 基因的抑制相整合。 mtDNA 基因的抑制是通过 MUC1-C 介导的 (i) mtDNA 转录所需的线粒体转录因子 A (TFAM) 下调和 (ii) 线粒体转录终止因子 3 (mTERF3) 诱导来解释的。为了支持抑制线粒体 ROS 产生的发病机制，靶向 MUC1-C 会增加 (i) mtDNA 基因转录、(ii) 超氧化物水平和 (iii) 自我更新能力的丧失。这些发现和 CSC 亚群的 scRNA-seq 分析表明，MUC1-C 通过整合糖酵解的激活与氧化磷酸化的抑制来调节自我更新和氧化还原平衡。© 2023 作者。

Activation of the MUC1-C protein promotes lineage plasticity, epigenetic reprogramming, and the cancer stem cell (CSC) state. The present studies performed on enriched populations of triple-negative breast cancer (TNBC) CSCs demonstrate that MUC1-C is essential for integrating activation of glycolytic pathway genes with self-renewal and tumorigenicity. MUC1-C further integrates the glycolytic pathway with suppression of mitochondrial DNA (mtDNA) genes encoding components of mitochondrial Complexes I-V. The repression of mtDNA genes is explained by MUC1-C-mediated (i) downregulation of the mitochondrial transcription factor A (TFAM) required for mtDNA transcription and (ii) induction of the mitochondrial transcription termination factor 3 (mTERF3). In support of pathogenesis that suppresses mitochondrial ROS production, targeting MUC1-C increases (i) mtDNA gene transcription, (ii) superoxide levels, and (iii) loss of self-renewal capacity. These findings and scRNA-seq analysis of CSC subpopulations indicate that MUC1-C regulates self-renewal and redox balance by integrating activation of glycolysis with suppression of oxidative phosphorylation.© 2023 The Authors.