PARG inhibition limits HCC progression and potentiates the efficacy of immune checkpoint therapy.

Abstract

BACKGROUND & AIMS:

Although the treatment of hepatocellular carcinoma (HCC) has been revolutionized by the advent of effective systemic therapies, the prognosis of patients with HCC remains dismal. Herein, we examined the pathophysiological role of PARG and assessed the utility of targeting dePARylation for HCC therapy.

METHODS:

The oncogenic function of PARG was evaluated in 2 orthotopic xenograft models and a Pargflox/flox mice model. The therapeutic efficacy of PARG inhibitors in combination with an anti-PD-1 antibody were assessed in murine orthotopic models. Microarray analysis was used to evaluate the pathological relevance of the PARG/DDB1/c-Myc/MMR axis.

RESULTS:

High PARG expression was strongly associated with poor HCC prognosis. Hepatocyte-specific PARG deletion significantly impaired liver tumorigenesis. PARG promoted HCC growth and metastasis through DDB1-dependent modulation of c-Myc. Specifically, PARG dePARylated DDB1 and consequently promoted DDB1 autoubiquitination, thus stabilizing the c-Myc protein in HCC cells. PARG downregulation attenuated c-Myc-induced MMR expression and PARG deficiency was correlated with a favorable prognosis in patients with HCC treated with anti-PD-1-based immunotherapy. In addition, PARG inhibitors could act in synergy with anti-PD-1 antibodies in orthotopic mouse models.

CONCLUSIONS:

PARG can act as an oncogene in HCC by modulating PARG/DDB1/c-Myc signaling and could be used as a biomarker to identify patients with HCC who may benefit from anti-PD-1 treatment. Our findings suggest that co-inhibition of PARG and PD-1 is an effective novel combination strategy for patients with HCC.

LAY SUMMARY:

The increase in deaths due to hepatocellular carcinoma (HCC) is a growing concern, with the mechanisms responsible for HCC development still incompletely understood. Herein, we identify a novel mechanism by which the protein PARG contributes to HCC development. Inhibition of PARG increased the efficacy of anti-PD-1 therapy (a type of immunotherapy) in HCC. These findings support the future clinical development of PARG inhibitors, potentially in combination with anti-PD-1 inhibitors.

• Authors: Mincheng Yu, Zheng Chen, Qiang Zhou, Bo Zhang, Jinlong Huang, Lei Jin, Binghai Zhou, Shuang Liu, Jiuliang Yan, Xiaoqiang Li, Wentao Zhang, Chunxiao Liu, Bo Hu, Peiyao Fu, Chenhao Zhou, Yongfeng Xu, Yongsheng Xiao, Jian Zhou, Jia Fan, Ning Ren, Mien-Chie Hung, Lei Guo, Hui Li, Qinghai Ye
• Journal: Journal of hepatology (J Hepatol) Vol. 77 Issue 1 Pg. 140-151 (07 2022) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 35157958 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Proto-Oncogene Proteins c-myc

Topics

• Animals
• Carcinoma, Hepatocellular (pathology)
• Cell Line, Tumor
• Humans
• Immunotherapy
• Liver Neoplasms (pathology)
• Mice
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Signal Transduction