HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity
HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity
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DOI：
10.1016/j.ccr.2007.04.001
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发表时间：
2007-05-01
期刊：
影响因子：
50.3
通讯作者：
Semenza, Gregg L.
中科院分区：
文献类型：
--
作者：
Zhang, Huafeng;Gao, Ping;Semenza, Gregg L.
许多癌细胞的特征是糖酵解增加和呼吸减少，即使在有氧条件下。这种代谢重编程背后的分子机制尚不清楚。在这里，我们表明，缺氧诱导因子1（HIF-1）负调控线粒体生物合成和O-2消耗的肾癌细胞缺乏冯希佩尔-林道肿瘤抑制（VHL）。HIF-1通过两种机制抑制C-MYC活性来介导这些作用。首先，HIF-1结合并激活MXI 1基因的转录，MXI 1基因编码C-MYC转录活性的阻遏物。其次，HIF-1促进C-MYC的MXI-1非依赖性、蛋白酶体依赖性降解。我们证明了编码辅激活因子PGC-1 β的基因的转录是C-MYC依赖性的，并且PGC-1 β表达的丧失是导致VHL缺陷型肾癌细胞呼吸减少的主要因素。
Many cancer cells are characterized by increased glycolysis and decreased respiration, even under aerobic conditions. The molecular mechanisms underlying this metabolic reprogramming are unclear. Here we show that hypoxia-inducible factor 1 (HIF-1) negatively regulates mitochondrial biogenesis and O-2 consumption in renal carcinoma cells lacking the von Hippel-Lindau tumor suppressor (VHL). HIF-1 mediates these effects by inhibiting C-MYC activity via two mechanisms. First, HIF-1 binds to and activates transcription of the MXI1 gene, which encodes a repressor of C-MYC transcriptional activity. Second, HIF-1 promotes MXI-1-independent, proteasome-dependent degradation of C-MYC. We demonstrate that transcription of the gene encoding the coactivator PGC-1 beta is C-MYC dependent and that loss of PGC-1 beta expression is a major factor contributing to reduced respiration in VHL-deficient renal carcinoma cells.