MYC-Regulated Mevalonate Metabolism Maintains Brain Tumor-Initiating Cells
Metabolic dysregulation drives tumor initiation in a subset of glioblastomas harboring isocitrate dehydrogenase (IDH) mutations, but metabolic alterations in glioblastomas with wild-type IDH are poorly understood. MYC promotes metabolic reprogramming in cancer, but targeting MYC has proven notoriously challenging. Here, we link metabolic dysregulation in patient-derived brain tumor–initiating cells (BTIC) to a nexus between MYC and mevalonate signaling, which can be inhibited by statin or 6-fluoromevalonate treatment. BTICs preferentially express mevalonate pathway enzymes, which we find regulated by novel MYC-binding sites, validating an additional transcriptional activation role of MYC in cancer metabolism. Targeting mevalonate activity attenuated RAS-ERK–dependent BTIC growth and self-renewal. In turn, mevalonate created a positive feed-forward loop to activate MYC signaling via induction of miR-33b. Collectively, our results argue that MYC mediates its oncogenic effects in part by altering mevalonate metabolism in glioma cells, suggesting a therapeutic strategy in this setting. Cancer Res; 77(18); 4947–60. ©2017 AACR.
Source: Cancer Research - Category: Cancer & Oncology Authors: Xiuxing Wang, Zhi Huang, Qiulian Wu, Briana C. Prager, Stephen C. Mack, Kailin Yang, Leo J.Y. Kim, Ryan C. Gimple, Yu Shi, Sisi Lai, Qi Xie, Tyler E. Miller, Christopher G. Hubert, Anne Song, Zhen Dong, Wenchao Zhou, Xiaoguang Fang, Zhe Zhu, Vaidehi Mahad Tags: Tumor and Stem Cell Biology Source Type: research
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