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

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 progression in vitro and in vivo. Our findings suggest that HB patients harboring activated β-catenin mutations and consequent DNPS upregulation, may be treated efficaciously with DNPS enzyme inhibitors like lometrexol. These novel findings bear major therapeutic implications for targeted precision medicine of HB.

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Publication Details

Journal
Cell Death and Disease
Published
2025-03-17
DOI
https://doi.org/10.1038/s41419-025-07502-6
Citations
4
Primary Topic
Biochemical and Molecular Research
Type
article
Field-Weighted Citation Impact
3.22
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article

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

Yehuda G. Assaraf, Yanyan Lin, Liang Zheng, Shuxuan Wang et al.
4 citations
Cell Death and Disease
Biochemical and Molecular Research
3.22
article

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

Yehuda G. Assaraf, Yanyan Lin, Liang Zheng, Shuxuan Wang, Liyuan Yang, Chunshuang Ma, Song Gu, Hongxiang Gao, Bin‐Bing S. Zhou, Xiaoyu Wu, Hui Li, Yao Chen, Liang Zhu, Jiquan Zhou, Yuhua Shan, Ya‐Bin Tang, Yan Xu, Ming Ding, Houshun Fang, Huiying Sun
article en
4 citations

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 progression in vitro and in vivo. Our findings suggest that HB patients harboring activated β-catenin mutations and consequent DNPS upregulation, may be treated efficaciously with DNPS enzyme inhibitors like lometrexol. These novel findings bear major therapeutic implications for targeted precision medicine of HB.

Cell Death and DiseaseVol. 16(1)
Fujian Medical University (CN), Technion – Israel Institute of Technology (IL), Shanghai Jiao Tong University (CN), Shanghai Children's Medical Center (CN), Ministry of Education (KR), Shanghai Children's Hospital (CN)
Good health and well-being
Openalex Percentile: Top 9%
Biochemical and Molecular Research
3.22
DOIOpen Access PDFOpenAlex
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