Hepatitis B virus-associated hepatocellular carcinoma with Smc5/6 complex deficiency is susceptible to PARP inhibitors.

Abstract

DNA repair processes represent attractive synthetic lethal targets because many cancers exhibit impaired DNA repair pathways, which leads to dependence on specific repair proteins. The finding that poly (ADP-ribose) polymerase (PARP)-1 inhibitors are highly effective against cancers with deficient homologous recombination highlights the potential of this approach. In hepatitis B viral (HBV) infection, degradation of the structural maintenance of the chromosome 5/6 (Smc5/6) complex, which plays a key role in repairing double-stranded DNA breaks by homologous recombination, is induced by HBV regulatory protein X (HBx). Here, we hypothesized that a deficiency in the Smc5/6 complex in HBV-associated hepatocellular carcinoma (HCC) increases susceptibility to PARP inhibitors via a deficiency in homologous recombination. We confirmed impaired double-stranded DNA break repair in HBx-expressing HCC cells using a sensitive reporter to monitor homologous recombination. Treatment with a PARP inhibitor was significantly more effective against HBx-expressing HCC cells, and overexpression of Smc5/6 prevented these effects. Overall, our results suggest that homologous recombination deficiency in HBV-associated HCC leads to increased susceptibility to PARP inhibitors.

• Authors: Kazuyoshi Funato, Motoyuki Otsuka, Kazuma Sekiba, Yu Miyakawa, Takahiro Seimiya, Chikako Shibata, Takahiro Kishikawa, Mitsuhiro Fujishiro
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 607 Pg. 89-95 (06 04 2022) ISSN: 1090-2104 [Electronic] United States
• PMID: 35367833 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Cell Cycle Proteins
• Chromosomal Proteins, Non-Histone
• Poly(ADP-ribose) Polymerase Inhibitors
• SMC5 protein, human
• Poly(ADP-ribose) Polymerases

Topics

• Carcinoma, Hepatocellular (drug therapy)
• Cell Cycle Proteins (metabolism)
• Chromosomal Proteins, Non-Histone (genetics)
• Hepatitis B virus (genetics, metabolism)
• Homologous Recombination
• Humans
• Liver Neoplasms (drug therapy, genetics)
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology)
• Poly(ADP-ribose) Polymerases (genetics)