Purine anabolism creates therapeutic vulnerability in hepatocellular carcinoma through m6A-mediated epitranscriptomic regulation

Author:

Hung Man Hsin1ORCID,Chang Ching Wen1ORCID,Wang Kathy Cheng1,Chaisaingmongkol Jittiporn23ORCID,Ruchirawat Mathuros23ORCID,Greten Tim F.45ORCID,Wang Xin Wei15ORCID

Affiliation:

1. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA

2. Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute, Bangkok, Thailand

3. Center of Excellence on Environmental Health and Toxicology (EHT), OPS, Ministry of Higher Education, Science, Research and Innovation, Bangkok, Thailand

4. Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

5. Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA

Abstract

Background and Aims: Purines are building blocks for the cellular genome, and excessive purine nucleotides are seen in tumors. However, how purine metabolism is dysregulated in tumors, and impacting tumorigenesis remains elusive. Approach and Results: Transcriptomic and metabolomic analyses of purine biosynthesis and purine degradation pathways were performed in the tumor and associated nontumor liver tissues obtained from 62 patients with HCC, one of the most lethal cancers worldwide. We found that most genes in purine synthesis are upregulated, while genes in purine degradation are inhibited in HCC tumors. High purine anabolism is associated with unique somatic mutational signatures linked to patient prognosis. Mechanistically, we discover that increasing purine anabolism promotes epitranscriptomic dysregulation of DNA damage repairing (DDR) machinery through upregulating RNA N6-methyladenosine (m6A) modification. High purine anabolic HCC is sensitive to DDR-targeting agents but not to standard HCC treatments, correlating with the clinical outcomes in 5 independent HCC cohorts containing 724 patients. We further showed that high purine anabolism determines the sensitivity to DDR-targeting agents in 5 HCC cell lines in vitro and in vivo. Conclusions: Our results reveal a central role of purine anabolism in regulating DDR, which could be therapeutically exploited in HCC.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Hepatology

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