Combinatorial targeting of MTHFD2 and PAICS in purine synthesis as a novel therapeutic strategy

• Published in: Cell death & disease Vol. 10; no. 11; pp. 786 - 16
• Main Authors: Cheung, Chantal Hoi Yin, Hsu, Chia-Lang, Tsuei, Chao-Yin, Kuo, Tzu-Ting, Huang, Chen-Tsung, Hsu, Wen-Ming, Chung, Yun-Hsien, Wu, Hsin-Yi, Hsu, Cheng-Chih, Huang, Hsuan-Cheng, Juan, Hsueh-Fen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17-10-2019; Springer Nature B.V
• Subjects: 13/31; 14/28; 38/109; 38/77; 631/154/555; 631/337/2019; 631/45/320; 631/67/2332; 631/80/83; 82/58; Aminohydrolases - genetics; Aminohydrolases - metabolism; Anisomycin; Antibodies; Biochemistry; Biomedical and Life Sciences; Carboxy-Lyases - genetics; Carboxy-Lyases - metabolism; Cell Biology; Cell Culture; Cell Cycle - physiology; Cell growth; Cell Growth Processes; Cell Line, Tumor; Cell proliferation; DNA biosynthesis; Folic acid; Gene expression; Gene Knockdown Techniques; Humans; Immunology; Life Sciences; Metabolic pathways; Metabolism; Metabolomics; Metastases; Methylenetetrahydrofolate Dehydrogenase (NADP) - genetics; Methylenetetrahydrofolate Dehydrogenase (NADP) - metabolism; Molecular Targeted Therapy; Multifunctional Enzymes - genetics; Multifunctional Enzymes - metabolism; Neural crest; Neuroblastoma; Neuroblastoma - genetics; Neuroblastoma - metabolism; Neuroblastoma - pathology; Neuroblastoma - therapy; Neuroblasts; Purines - biosynthesis; Toxicity; Transcription; Transcriptome; Transfection; Up-Regulation
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-2033-z

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.