Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia.
Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia.
复制标题
糖酵解看门人PDK1在缺氧条件下重新编程乳腺癌干细胞
作者：
Peng F;Wang JH;Fan WJ;Meng YT;Li MM;Li TT;Cui B;Wang HF;Zhao Y;An F;Guo T;Liu XF;Zhang L;Lv L;Lv DK;Xu LZ;Xie JJ;Lin WX;Lam EW;Xu J;Liu Q
糖酵解对于癌症干细胞重编程至关重要;然而，潜在的调控机制仍然难以捉摸。在这里，我们发现丙酮酸脱氢酶激酶1（PDK 1）在乳腺癌干细胞（BCSC）中富集，而PDK 1的缺失显著减少ALDH+亚群，降低干细胞相关转录因子的表达，并抑制球体形成能力和肿瘤生长。相反，高水平的PDK 1增强BCSC的特性，并与总生存率低相关。在小鼠异种移植肿瘤中，PDK 1在缺氧区域积累并激活糖酵解以促进干细胞样性状。此外，通过筛选PDK 1阳性组织中与缺氧相关的长链非编码RNA（lncRNA），我们发现lncRNA H19负责糖酵解和BCSC维持。此外，H19敲低降低了缺氧时PDK 1的表达，并且PDK 1的消融在体外和体内抵消了H19介导的糖酵解和自我更新能力。因此，H19和PDK 1表达在原发性乳腺癌中表现出强相关性。H19作为一种竞争性内源性RNA螯合miRNA let-7释放缺氧诱导因子1α，导致PDK 1表达增加。最后，阿司匹林通过抑制H19和PDK 1显著减弱糖酵解和癌干样特征。因此，这些新的发现表明，糖酵解看门人PDK 1在BCSC重编程中具有关键作用，并为乳腺恶性肿瘤提供了潜在的治疗策略。
Glycolysis is critical for cancer stem cell reprogramming; however, the underlying regulatory mechanisms remain elusive. Here, we show that pyruvate dehydrogenase kinase 1 (PDK1) is enriched in breast cancer stem cells (BCSCs), whereas depletion of PDK1 remarkably diminishes ALDH+ subpopulations, decreases stemness-related transcriptional factor expression, and inhibits sphere-formation ability and tumor growth. Conversely, high levels of PDK1 enhance BCSC properties and are correlated with poor overall survival. In mouse xenograft tumor, PDK1 is accumulated in hypoxic regions and activates glycolysis to promote stem-like traits. Moreover, through screening hypoxia-related long non-coding RNAs (lncRNAs) in PDK1-positive tissue, we find that lncRNA H19 is responsible for glycolysis and BCSC maintenance. Furthermore, H19 knockdown decreases PDK1 expression in hypoxia, and ablation of PDK1 counteracts H19-mediated glycolysis and self-renewal ability in vitro and in vivo. Accordingly, H19 and PDK1 expression exhibits strong correlations in primary breast carcinomas. H19 acting as a competitive endogenous RNA sequesters miRNA let-7 to release Hypoxia-inducible factor 1α, leading to an increase in PDK1 expression. Lastly, aspirin markedly attenuates glycolysis and cancer stem-like characteristics by suppressing both H19 and PDK1. Thus, these novel findings demonstrate that the glycolysis gatekeeper PDK1 has a critical role in BCSC reprogramming and provides a potential therapeutic strategy for breast malignancy.
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影响因子：
50.3
作者：
Chae YC;Vaira V;Caino MC;Tang HY;Seo JH;Kossenkov AV;Ottobrini L;Martelli C;Lucignani G;Bertolini I;Locatelli M;Bryant KG;Ghosh JC;Lisanti S;Ku B;Bosari S;Languino LR;Speicher DW;Altieri DC
通讯作者：
Altieri DC
影响因子：
--
作者：
Denise C;Paoli P;Calvani M;Taddei ML;Giannoni E;Kopetz S;Kazmi SM;Pia MM;Pettazzoni P;Sacco E;Caselli A;Vanoni M;Landriscina M;Cirri P;Chiarugi P
通讯作者：
Chiarugi P
影响因子：
29
作者：
Folmes CD;Nelson TJ;Martinez-Fernandez A;Arrell DK;Lindor JZ;Dzeja PP;Ikeda Y;Perez-Terzic C;Terzic A
通讯作者：
Terzic A
Nanog通过氧化磷酸化和脂肪酸代谢的肿瘤性变化来代谢重新编程肿瘤发射类样细胞。
影响因子：
29
作者：
Chen CL;Uthaya Kumar DB;Punj V;Xu J;Sher L;Tahara SM;Hess S;Machida K
通讯作者：
Machida K
影响因子：
10.5
作者：
Janiszewska, Michalina;Suva, Mario L.;Stamenkovic, Ivan
通讯作者：
Stamenkovic, Ivan