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

Abstract

MYCN amplification drives the development of neuronal cancers in children and adults. Given the challenge in therapeutically targeting MYCN directly, we searched for MYCNactivated metabolic pathways as potential drug targets. Here we report that neuroblastoma cells with MYCN amplification show increased transcriptional activation of the serine-glycineone-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 FBXW7mediated 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 Materials and Methods Cell lines and cell culture Neuroblastoma cell lines BE(2)

Influenza infection rewires energy metabolism and induces browning features in adipose cells and tissues

“…The upstream regulators predicted to be associated with the genes exclusively upregulated in preadipocytes included activating transcription factor 4 (ATF4), UCP1, and MYC (Supplementary Table 6). ATF4 and MYC form a positive feedback loop for transcriptional activation of the SGOC pathway 50 , and UCP1 was reported to induce Atf4 expression 51 .…”

Glycine decarboxylase is a transcriptional target of MYCN required for neuroblastoma cell proliferation and tumorigenicity

“…1a) is a common feature of metabolic reprogramming in various types of cancers. Genes encoding enzymes of this pathway are frequently overexpressed in cancers, as a result of genomic amplification [16,17] or transcriptional activation [18][19][20][21][22][23][24] . The SGOC pathway links the glycolytic intermediate 3-phosphoglycerate to the production of serine, glycine, and the one-carbon carriers 5,10-methylene-tetrahydrofolate (5,10-MTHF) and 10-formyl-THF, which contribute carbon and nitrogen to purine nucleotide and thymidylate synthesis.…”

PHGDH as a mechanism for resistance in metabolically-driven cancers

“…Based on the potential role of c-Myc in resistance to HIF2α inhibitors, the role of NMYC in systems associated with PHGDH has been explored. NMYC activates ATF4, subsequently increasing PHGDH expression and activating a dependence on the serine biosynthetic pathway [78][79][80] . Proteasome inhibitors downregulate c-Myc, and have therefore been utilized to combat c-Myc-driven cancers [81] .…”