Therapeutic targeting de novo purine biosynthesis driven by β-catenin-dependent PPAT upregulation in hepatoblastoma.

ABSTRACT: De novo purine biosynthesis (DNPS) was previously shown to be aberrantly activated in many cancers. However, the activity of DNPS pathway and its underlying regulatory mechanism in hepatoblastoma (HB) remain poorly understood. Herein, we discovered that the expression of PPAT, the rate-limiting enzyme in DNPS, was markedly upregulated in HB, leading to an augmented purine flux via DNPS, thereby promoting both HB cell proliferation and migration. Furthermore, we found that activated mutant β-catenin, a dominant driver of HB, transcriptionally activated PPAT expression, hence stimulating DNPS and constituting a druggable metabolic vulnerability in HB. Consistently, pharmacological targeting using a DNPS inhibitor lometrexol or genetic repressing the enhanced DNPS markedly blocked HB progress

SUBMITTER: Ding M 

PROVIDER: S-EPMC11914223 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature