MUC1 mucin stabilizes and activates hypoxia-inducible factor 1 alpha to regulate metabolism in pancreatic cancer
MUC1 mucin stabilizes and activates hypoxia-inducible factor 1 alpha to regulate metabolism in pancreatic cancer
复制标题
DOI：
10.1073/pnas.1203339109
复制
发表时间：
2012-08-21
影响因子：
11.1
通讯作者：
Singh, Pankaj K.
中科院分区：
文献类型：
--
作者：
Chaika, Nina V.;Gebregiworgis, Teklab;Singh, Pankaj K.
糖代谢异常是癌症的特征之一，它促进了癌细胞的存活和增殖。在这里，我们证明了MUC1，一种大的I型跨膜蛋白，在包括胰腺癌在内的几种癌症中过表达，调节癌细胞的代谢，促进癌细胞的生长特性。MUC1是直接参与糖代谢的多个基因的启动子元件，并调节其表达。此外，MUC1的表达增强了胰腺癌细胞的糖酵解活性。我们还证明，在胰腺癌原位种植模型中，MUC1的表达增强了体内葡萄糖摄取和参与葡萄糖摄取和代谢的基因的表达。已知的MUC1胞质尾巴通过与不同基因启动子元件上的几个转录因子/共调节因子相互作用而激活多条信号通路。我们的结果表明，MUC1通过调节低氧诱导因子-1α(HIF-1α)的表达/稳定性和活性来调节胰腺癌细胞的低氧反应。MUC1与HIF-1α和p300在物理上相互作用，并在蛋白质水平上稳定前者。通过芯片实验，我们证明了MUC1以一种低氧依赖的方式促进HIF-1α和p300在糖酵解基因启动子上的募集。此外，通过代谢组学研究，我们证明了MUC1调节葡萄糖和氨基酸代谢途径中的多种代谢物中间体。因此，我们的研究表明，MUC1作为代谢程序的主调节器，促进低氧环境中的代谢变化，帮助肿瘤细胞在这种条件下存活和增殖。
Aberrant glucose metabolism is one of the hallmarks of cancer that facilitates cancer cell survival and proliferation. Here, we demonstrate that MUC1, a large, type I transmembrane protein that is overexpressed in several carcinomas including pancreatic adenocarcinoma, modulates cancer cell metabolism to facilitate growth properties of cancer cells. MUC1 occupies the promoter elements of multiple genes directly involved in glucose metabolism and regulates their expression. Furthermore, MUC1 expression enhances glycolytic activity in pancreatic cancer cells. We also demonstrate that MUC1 expression enhances in vivo glucose uptake and expression of genes involved in glucose uptake and metabolism in orthotopic implantation models of pancreatic cancer. The MUC1 cytoplasmic tail is known to activate multiple signaling pathways through its interactions with several transcription factors/coregulators at the promoter elements of various genes. Our results indicate that MUC1 acts as a modulator of the hypoxic response in pancreatic cancer cells by regulating the expression/stability and activity of hypoxia-inducible factor-1 alpha (HIF-1 alpha). MUC1 physically interacts with HIF-1 alpha and p300 and stabilizes the former at the protein level. By using a ChIP assay, we demonstrate that MUC1 facilitates recruitment of HIF-1 alpha and p300 on glycolytic gene promoters in a hypoxia-dependent manner. Also, by metabolomic studies, we demonstrate that MUC1 regulates multiple metabolite intermediates in the glucose and amino acid metabolic pathways. Thus, our studies indicate that MUC1 acts as a master regulator of the metabolic program and facilitates metabolic alterations in the hypoxic environments that help tumor cells survive and proliferate under such conditions.