Hypoxia-inducible factor 1 mediates TAZ expression and nuclear localization to induce the breast cancer stem cell phenotype.
Hypoxia-inducible factor 1 mediates TAZ expression and nuclear localization to induce the breast cancer stem cell phenotype.
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DOI：
10.18632/oncotarget.2997
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发表时间：
2014-12-30
期刊：
影响因子：
--
通讯作者：
Semenza GL
中科院分区：
文献类型：
--
作者：
Xiang L;Gilkes DM;Hu H;Takano N;Luo W;Lu H;Bullen JW;Samanta D;Liang H;Semenza GL
肿瘤内缺氧与乳腺癌转移和患者死亡率有关，可增加乳腺癌干细胞(BCSCs)的比例，但其潜在的分子机制尚未阐明。在这里，我们报道低氧诱导因子1(HIF-1)通过两种不同的机制触发TAZ的表达和活性，TAZ是维持BCSC所需的转录辅助激活因子。首先，HIF-1直接与WWTR1基因结合，激活TAZ基因的转录。其次，HIF-1激活SIAH1基因的转录，该基因编码一种泛素蛋白连接酶，在低氧诱导的泛素化和蛋白酶体依赖的LATS2降解中是必需的，LATS2是一种抑制TAZ核定位的激酶。短发夹状核糖核酸抑制HIF-1α、TAZ或SIAH1mRNA的表达，阻断了BCSCs对低氧的富集性。人类乳腺癌数据库分析显示，TAZ和HIF-1靶基因的表达增加(高于中位数)，但两者都不是单独的，与显著增加的患者死亡率相关。综上所述，这些结果建立了诱导BCSC响应低氧表型的分子机制。
Intratumoral hypoxia, which is associated with breast cancer metastasis and patient mortality, increases the percentage of breast cancer stem cells (BCSCs) but the underlying molecular mechanisms have not been delineated. Here we report that hypoxia-inducible factor 1 (HIF-1) triggers the expression and activity of TAZ, a transcriptional co-activator that is required for BCSC maintenance, through two discrete mechanisms. First, HIF-1 binds directly to the WWTR1 gene and activates transcription of TAZ mRNA. Second, HIF-1 activates transcription of the SIAH1 gene, which encodes a ubiquitin protein ligase that is required for the hypoxia-induced ubiquitination and proteasome-dependent degradation of LATS2, a kinase that inhibits the nuclear localization of TAZ. Inhibition of HIF-1α, TAZ, or SIAH1 expression by short hairpin RNA blocked the enrichment of BCSCs in response to hypoxia. Human breast cancer database analysis revealed that increased expression (greater than the median) of both TAZ and HIF-1 target genes, but neither one alone, is associated with significantly increased patient mortality. Taken together, these results establish a molecular mechanism for induction of the BCSC phenotype in response to hypoxia.
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