Myc posttranscriptionally induces HIF1 protein and target gene expression in normal and cancer cells.
Myc posttranscriptionally induces HIF1 protein and target gene expression in normal and cancer cells.
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DOI：
10.1158/0008-5472.can-11-2371
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发表时间：
2012-02-15
期刊：
影响因子：
11.2
通讯作者：
Cole MD
中科院分区：
文献类型：
--
作者：
Doe MR;Ascano JM;Kaur M;Cole MD
c-Myc在肿瘤中经常过表达，在调节癌症代谢中起重要作用。缺氧诱导因子-1（HIF 1）是缺氧反应的主要调节因子，通过上调糖酵解途径和抑制线粒体呼吸来增强肿瘤发生并影响代谢。Myc和HIF-1的失调共同为增殖的癌细胞提供了代谢优势，并促成了瓦尔堡效应。在这里，我们表明，Myc的过表达显着稳定的α亚基的HIF 1（HIF 1 α）在常氧条件下，并增强HIF 1 α积累在缺氧条件下的细胞。Myc对HIF 1 α的转录后调节导致HIF 1 α基因靶点的诱导。常氧HIF 1 α蛋白表达也依赖于Myc。在功能上，HIF 1 α表达是Myc诱导的非贴壁依赖性生长和细胞增殖所必需的。HIF 1 α的Myc依赖性稳定涉及与VHL复合物结合的破坏或翻译后蛋白质修饰。总之，我们的研究结果揭示了Myc和HIF 1之间以前未表征的调节关系，这对癌症代谢和发展具有重要意义。
c-Myc is frequently overexpressed in tumors and plays an important role in the regulation of cancer metabolism. Hypoxia-inducible factor-1 (HIF1), the master regulator of the hypoxic response, enhances tumorigenesis and influences metabolism via upregulation of the glycolytic pathway and suppression of mitochondrial respiration. Together, deregulated Myc and HIF1 cooperate to lend metabolic advantages to proliferating cancer cells and contribute to the Warburg Effect. Here we show that overexpression of Myc significantly stabilizes the alpha subunit of HIF1 (HIF1alpha) under normoxic conditions and enhances HIF1alpha accumulation under hypoxic conditions in cells. Post-transcriptional regulation of HIF1α by Myc led to the induction of HIF1α gene targets. Normoxic HIF1α protein expression was also dependent on Myc. Functionally; HIF1α expression was required for Myc-induced anchorage-independent growth and cell proliferation. Myc-dependent stabilization of HIF1α involved either disruption of binding to the VHL complex or post-translational protein modifications. Taken together, our findings uncover a previously uncharacterized regulatory relationship between Myc and HIF1 that has important implications for cancer metabolism and development.