High Expression of G9a Induces Cisplatin Resistance in Hepatocellular Carcinoma

Document Type : Original Article


1 Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China

2 Department of Hepatobiliary and Pancreatic Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China


Objective: Chemotherapeutic drug resistance is the main obstacle that affects the efficacy of current therapies of
hepatocellular carcinoma (HCC), which needs to be addressed urgently. High expression of histone methyltransferase
G9a was reported to play a pivotal role in the progression of HCC. Regulatory mechanism of aberrant activation of G9a
in HCC and the association with subsequent cisplatin (DDP) resistance still remains ambiguous. This study strived to
investigate mechanism of G9a overexpression and its impact on cisplatin resistance in HCC cells.
Materials and Methods: In this experimental study, we investigated effects of different concentrations of cisplatin in
combination with BIX-01294 or PR-619 on viability and apoptosis of HuH7 and SNU387 cells via CCK-8 kit and flow
cytometric analysis, respectively. Colony formation capacity was applied to evaluate effect of cisplatin with or without
BIX-01294 on cell proliferation, and western blotting was used to verify expression level of the related proteins. Global
mRNA expression profile analysis was adopted to identify differentially expressed genes associated with overexpression
of G9a.
Results: We observed that overexpression of G9a admittedly promoted cisplatin resistance in HCC cells. Global
mRNA expression profile analysis after G9a inhibition showed that DNA repair and cell cycle progression were downregulated.
Moreover, we identified that deubiquitination enzymes (DUBs) stabilized high expression of G9a in HCC
through deubiquitination. Additionally, cisplatin could significantly inhibit proliferation of DUBs-deficient HCC cells, while
promoting their apoptosis.
Conclusion: Collectively, our data indicated that DUBs stabilize G9a through deubiquitination, thereby participating in
the cisplatin resistance of HCC cells. The elucidation of this mechanism contributes to propose a potential alternative
intervention strategy for the treatment of HCC patients harboring high G9a levels.


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