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MYC-Regulated Mevalonate Metabolism Maintains Brain Tumor-Initiating Cells

MYC-Regulated Mevalonate Metabolism Maintains Brain Tumor-Initiating Cells

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, etc.

Cancer Res. 2017 Sep 15;77(18):4947-4960.

PMID: 28729418

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP2822777	6-Fluoromevalonate		2822-77-7	Price

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