MYCN STIMULATES GLYCINE DECARBOXYLASE (GLDC) IN NEUROBLASTOMA TO PROMOTE TUMORIGENESIS

Abstract

Genomic amplification of the oncogene MYCN is a major driver in the development of high-risk neuroblastoma, a pediatric cancer with poor prognosis. Given the challenge in targeting MYCN directly for therapy, we sought to identify MYCN-dependent metabolic vulnerabilities that can be targeted therapeutically. Here, we report that the gene encoding glycine decarboxylase (GLDC), which catalyzes the first and rate-limiting step in glycine breakdown with the production of one-carbon unit 5,10-methylene-tetrahydrofolate, is a direct transcriptional target of MYCN. GLDC expression is markedly elevated in MYCN-amplified neuroblastoma tumors and cell lines. This transcriptional upregulation of GLDC expression is of functional significance, as GLDC depletion by RNA interference inhibits the proliferation and tumorigenicity of MYCN-amplified neuroblastoma cell lines. Metabolomic profiling reveals that GLDC knockdown disrupts purine and central carbon metabolism and reduces citrate production, leading to a decrease in the steady-state levels of cholesterol and fatty acids, which are essential to sustain cell proliferation. In addition, microarray gene expression profiling shows that GLDC silencing downregulates genes involved in regulation of cell proliferation. These findings suggest that GLDC is a key player in MYCN-regulated cancer metabolism and a potential drug target in the treatment of high-risk neuroblastoma.