| Autor: |
Cheung CHY; Department of Life Science, National Taiwan University, Taipei, 10617, Taiwan., Hsu CL; Department of Life Science, National Taiwan University, Taipei, 10617, Taiwan.; Department of Medical Research, National Taiwan University Hospital, Taipei, 10002, Taiwan., Tsuei CY; Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, 10617, Taiwan., Kuo TT; Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, 10617, Taiwan., Huang CT; Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, 10617, Taiwan., Hsu WM; Department of Surgery, National Taiwan University Hospital and College of Medicine National Taiwan University, Taipei, 10017, Taiwan., Chung YH; Department of Life Science, National Taiwan University, Taipei, 10617, Taiwan., Wu HY; Department of Chemistry, National Taiwan University, Taipei, 10617, Taiwan., Hsu CC; Department of Chemistry, National Taiwan University, Taipei, 10617, Taiwan., Huang HC; Institute of Biomedical Informatics, National Yang-Ming University, Taipei, 11221, Taiwan. hsuancheng@ym.edu.tw., Juan HF; Department of Life Science, National Taiwan University, Taipei, 10617, Taiwan. yukijuan@ntu.edu.tw.; Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, 10617, Taiwan. yukijuan@ntu.edu.tw.; Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, 10617, Taiwan. yukijuan@ntu.edu.tw. |
| Abstrakt: |
MYCN-amplified (MNA) neuroblastoma is an aggressive neural crest-derived pediatric cancer. However, MYCN is indispensable for development and transcriptionally regulates extensive network of genes. Integrating anti-MYCN ChIP-seq and gene expression profiles of neuroblastoma patients revealed the metabolic enzymes, MTHFD2 and PAICS, required for one-carbon metabolism and purine biosynthesis were concomitantly upregulated, which were more susceptible to metastatic neuroblastoma. Moreover, we found that MYCN mediated the folate cycle via MTHFD2, which contributed one-carbon unit to enhance purine synthesis, and further regulated nucleotide production by PAICS in response to cancer progression. Dual knockdown of the MYCN-targeted gene pair, MTHFD2 and PAICS, in MNA neuroblastoma cells synergically reduced cell proliferation, colony formation, migration ability, and DNA synthesis. By systematically screening the compound perturbagens, the gene expression levels of MTHFD2 and PAICS were specifically suppressed by anisomycin and apicidin across cell lines, and our co-treatment results also displayed synergistic inhibition of MNA neuroblastoma cell proliferation. Collectively, targeting a combination of MYCN-targeted genes that interrupts the interconnection of metabolic pathways may overcome drug toxicity and improve the efficacy of current therapeutic agents in MNA neuroblastoma. |
