Journal article
MYC-Regulated Mevalonate Metabolism Maintains Brain Tumor-Initiating Cells
Cancer research (Chicago, Ill.), Vol.77(18), pp.4947-4960
09/15/2017
DOI: 10.1158/0008-5472.CAN-17-0114
PMCID: PMC5600855
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 IDHare poorly understood. MYCpromotes 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 meva-lonate 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. (C)2017 AACR.
Details
- Title: Subtitle
- MYC-Regulated Mevalonate Metabolism Maintains Brain Tumor-Initiating Cells
- Creators
- Xiuxing Wang - Cleveland Clinic Lerner College of MedicineZhi Huang - Cleveland Clinic Lerner College of MedicineQiulian Wu - Cleveland Clinic Lerner College of MedicineBriana C. Prager - Cleveland Clinic Lerner College of MedicineStephen C. Mack - Cleveland Clinic Lerner College of MedicineKailin Yang - Cleveland Clinic Lerner College of MedicineLeo J. Y. Kim - Cleveland Clinic Lerner College of MedicineRyan C. Gimple - Cleveland Clinic Lerner College of MedicineYu Shi - Cleveland Clinic Lerner College of MedicineSisi Lai - Cleveland Clinic Lerner College of MedicineQi Xie - Cleveland Clinic Lerner College of MedicineTyler E. Miller - Cleveland Clinic Lerner College of MedicineChristopher G. Hubert - Cleveland Clinic Lerner College of MedicineAnne Song - Cleveland Clinic Lerner College of MedicineZhen Dong - Cleveland Clinic Lerner College of MedicineWenchao Zhou - Cleveland Clinic Lerner College of MedicineXiaoguang Fang - Cleveland Clinic Lerner College of MedicineZhe Zhu - Cleveland Clinic Lerner College of MedicineVaidehi Mahadev - Cleveland Clinic Lerner College of MedicineShideng Bao - Cleveland Clinic Lerner College of MedicineJeremy N. Rich - Cleveland Clinic Lerner College of Medicine
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.77(18), pp.4947-4960
- DOI
- 10.1158/0008-5472.CAN-17-0114
- PMID
- 28729418
- PMCID
- PMC5600855
- NLM abbreviation
- Cancer Res
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 14
- Grant note
- CA197718; CA154130; CA169117; CA171652; NS087913; NS089272; CA184090; NS091080; NS099175 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01CA154130 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R01NS091080 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) T32GM007250 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS)
- Language
- English
- Date published
- 09/15/2017
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984696723302771
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