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MetabolicReprogramming by MYCNConfers Dependence ontheSerine-Glycine-One-Carbon BiosyntheticPathway Yingfeng XiaBingwei YeJane Ding2019 год

Metabolic Reprogramming by MYCN Confers Dependence on the Serine-Glycine-One-Carbon Biosynthetic Pathway
статья из журнала

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Аннотация: MYCN amplification drives the development of neuronal cancers in children and adults. Given the challenge in therapeutically targeting MYCN directly, we searched for MYCN-activated metabolic pathways as potential drug targets. Here we report that neuroblastoma cells with MYCN amplification show increased transcriptional activation of the serine-glycine-one-carbon (SGOC) biosynthetic pathway and an increased dependence on this pathway for supplying glucose-derived carbon for serine and glycine synthesis. Small molecule inhibitors that block this metabolic pathway exhibit selective cytotoxicity to MYCN-amplified cell lines and xenografts by inducing metabolic stress and autophagy. Transcriptional activation of the SGOC pathway in MYCN-amplified cells requires both MYCN and ATF4, which form a positive feedback loop, with MYCN activation of ATF4 mRNA expression and ATF4 stabilization of MYCN protein by antagonizing FBXW7-mediated MYCN ubiquitination. Collectively, these findings suggest a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited as a strategy for selective cancer therapy. SIGNIFICANCE: This study identifies a MYCN-dependent metabolic vulnerability and suggests a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited for cancer therapy.See related commentary by Rodriguez Garcia and Arsenian-Henriksson, p. 3818.
Год издания: 2019
Авторы: Yingfeng Xia, Bingwei Ye, Jane Ding, Yajie Yu, Ahmet Alptekin, Muthusamy Thangaraju, Puttur D. Prasad, Zhi-Chun Ding, Eun Jeong Park, Jeong‐Hyeon Choi, Bei Gao, Oliver Fiehn, Chunhong Yan, Zheng Dong, Yunhong Zha, Han‐Fei Ding
Издательство: American Association for Cancer Research
Источник: Cancer Research
Ключевые слова: Epigenetics and DNA Methylation, Pancreatic function and diabetes, Genetics and Neurodevelopmental Disorders
Другие ссылки: Cancer Research (HTML)
PubMed Central (HTML)
doi.org (HTML)
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aacr.figshare.com (PDF)
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eScholarship (California Digital Library) (PDF)
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