Highlights
- •PARG is upregulated in HCC tissues and predicts poor prognosis.
- •PARG regulation of c-MYC expression is dependent on PARG-mediated DDB1 degradation in HCC.
- •PARG promotes growth and metastasis of HCC via a newly identified PARG/DDB1/c-Myc signaling axis.
- •PARG promotes MMR expression and could potentially be used to predict which patients might benefit from anti-PD-1 treatment.
- •PARG inhibition potentiates the efficacy of PD-1 blockade in a murine HCC model.
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.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: February 11, 2022
Accepted:
January 28,
2022
Received in revised form:
January 23,
2022
Received:
March 27,
2021
Footnotes
Author names in bold designate shared co-first authorship
Identification
Copyright
© 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
