Overexpression of nucleotide metabolic enzyme DUT in hepatocellular carcinoma potentiates a therapeutic opportunity through targeting its dUTPase activity.

Abstract

Uracil misincorporation during DNA replication is a major cell toxic event, of which cancer cells overcome by activating the dUTPase enzyme. The DUT gene is the only known dUTPase in human. Despite reports on common upregulations in cancers, the role of DUT in human hepatocellular carcinoma (HCC) remains largely undetermined. In this study, we investigated the mechanism underlying DUT biology in HCC and tumor susceptibility to drug targeting dUTPase. Overexpression of DUT was found in 42% of HCC tumors and correlated with advanced stage HCC. Knockout of DUT in HCC cell lines showed suppressed proliferation through cell cycle arrest and a spontaneous induction of DNA damage. A protective effect from oxidative stress was also demonstrated in both knockout and overexpression DUT assays. Transcriptome analysis highlighted the NF-κB survival signaling as the downstream effector pathway of DUT in overriding oxidative stress-induced cell death. Interestingly, stably expressed DUT in liver progenitor organoids conferred drug resistance to TKI Sorafenib. Targeting dUTPase activity by TAS-114, could potentiate suppression of HCC growth that synergized with Sorafenib for better treatment sensitivity. In conclusion, upregulated DUT represents a nucleotide metabolic weakness and therapeutic opportunity in HCC.

• Authors: Mingjing Xu, Yue Liu, Ho Lee Wan, Alissa M Wong, Xiaofan Ding, Wenxing You, Wing Sze Lo, Kelvin K-C Ng, Nathalie Wong
• Journal: Cancer letters (Cancer Lett) Vol. 548 Pg. 215898 (11 01 2022) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 36075487 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• NF-kappa B
• Nucleotides
• Uracil
• Sorafenib
• Pyrophosphatases
• dUTP pyrophosphatase

Topics

• Carcinoma, Hepatocellular (drug therapy, genetics)
• Cell Line, Tumor
• Humans
• Liver Neoplasms (drug therapy, genetics)
• NF-kappa B
• Nucleotides
• Pyrophosphatases
• Sorafenib (pharmacology)
• Uracil (metabolism)