Targeting the De Novo Purine Synthesis Pathway Through Adenylosuccinate Lyase Depletion Impairs Liver Cancer Growth by Perturbing Mitochondrial Function
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nihms-1711913.pdf
Description
Accepted version
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4.1 MB
Format
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Author(s)
Jiang, Tingting
Sánchez-Rivera, Francisco J
Soto-Feliciano, Yadira M
Yang, Qiyuan
Song, Chun-Qing
Bhuatkar, Arjun
Haynes, Cole M
Hemann, Michael T
Xue, Wen
Date Issued
2021
Journal
Hepatology
Publisher
Wiley
Citation
Jiang, Tingting, Sánchez-Rivera, Francisco J, Soto-Feliciano, Yadira M, Yang, Qiyuan, Song, Chun-Qing et al. 2021. "Targeting the De Novo Purine Synthesis Pathway Through Adenylosuccinate Lyase Depletion Impairs Liver Cancer Growth by Perturbing Mitochondrial Function." Hepatology, 74 (1).
Version
Author's final manuscript
Abstract
BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is among the most common cancer types worldwide, yet patients with HCC have limited treatment options. There is an urgent need to identify drug targets that specifically inhibit the growth of HCC cells. APPROACH AND RESULTS: We used a CRISPR library targeting ~2,000 druggable genes to perform a high-throughput screen and identified adenylosuccinate lyase (ADSL), a key enzyme involved in the de novo purine synthesis pathway, as a potential drug target for HCC. ADSL has been implicated as a potential oncogenic driver in some cancers, but its role in liver cancer progression remains unknown. CRISPR-mediated knockout of ADSL impaired colony formation of liver cancer cells by affecting AMP production. In the absence of ADSL, the growth of liver tumors is retarded in vivo. Mechanistically, we found that ADSL knockout caused S-phase cell cycle arrest not by inducing DNA damage but by impairing mitochondrial function. Using data from patients with HCC, we also revealed that high ADSL expression occurs during tumorigenesis and is linked to poor survival rate. CONCLUSIONS: Our findings uncover the role of ADSL-mediated de novo purine synthesis in fueling mitochondrial ATP production to promote liver cancer cell growth. Targeting ADSL may be a therapeutic approach for patients with HCC.
MIT Department
Whitehead Institute for Biomedical Research
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DOI of Published Version
https://doi.org/10.1002/HEP.31685
