Transcription factor NRF2 orchestrates a cellular defense against oxidative stress and, so far, has been involved in tumor progression by providing a metabolic adaptation to tumorigenic demands and resistance to chemotherapeutics. In this study, we discover that NRF2 also propels tumorigenesis in gliomas and glioblastomas by inducing the expression of the transcriptional co-activator TAZ, a protein of the Hippo signaling pathway that promotes tumor growth. The expression of the genes encoding NRF2 (NFE2L2) and TAZ (WWTR1) showed a positive correlation in 721 gliomas from The Cancer Genome Atlas database. Moreover, NRF2 and TAZ protein levels also correlated in immunohistochemical tissue arrays of glioblastomas. Genetic knock-down of NRF2 decreased, while NRF2 overexpression or chemical activation with sulforaphane, increased TAZ transcript and protein levels. Mechanistically, we identified several NRF2-regulated functional enhancers in the regulatory region of WWTR1. The relevance of the new NRF2/TAZ axis in tumorigenesis was demonstrated in subcutaneous and intracranial grafts. Thus, intracranial inoculation of NRF2-depleted glioma stem cells did not develop tumors as determined by magnetic resonance imaging. Forced TAZ overexpression partly rescued both stem cell growth in neurospheres and tumorigenicity. Hence, NRF2 not only enables tumor cells to be competent to proliferate but it also propels tumorigenesis by activating the TAZ-mediated Hippo transcriptional program.

转录因子NRF2协调细胞对氧化应激的防御作用，到目前为止，它已通过提供对致瘤需求的代谢适应和对化学疗法的抗性而参与了肿瘤的发展。在这项研究中，我们发现NRF2还通过诱导转录共激活因子TAZ（一种促进肿瘤生长的Hippo信号通路蛋白）的表达来促进神经胶质瘤和成胶质细胞瘤的肿瘤发生。NRF2（NFE2L2）和TAZ（WWTR1）编码基因的表达。）在癌症基因组图谱数据库中的721个神经胶质瘤中显示出正相关。此外，在成胶质细胞瘤的免疫组织化学组织阵列中，NRF2和TAZ蛋白水平也相关。NRF2的基因敲低减少，而NRF2的过表达或萝卜硫烷的化学激活会增加TAZ转录本和蛋白质水平。从机制上讲，我们在WWTR1的调控区域中鉴定了几种NRF2调控的功能增强子。在皮下和颅内移植物中证实了新的NRF2 / TAZ轴在肿瘤发生中的相关性。因此，如磁共振成像所确定的那样，颅内接种NRF2耗尽的神经胶质瘤干细胞不会形成肿瘤。强迫的TAZ过表达可部分挽救神经球干细胞的生长和致瘤性。因此，NRF2不仅使肿瘤细胞具有增殖能力，而且还可以通过激活TAZ介导的Hippo转录程序来促进肿瘤发生。