Targeting PCNA/PARP1 axis inhibits the malignant progression of hepatocellular carcinoma

Jipin Li Tao Yong Yali Chen Tingyu Zeng Kaifeng Zhang Shuping Wang ^* Youcheng Zhang

• Lanzhou University, Lanzhou, China

Proliferating cell nuclear antigen (PCNA) is associated with the proliferation and recurrence of various cancers, and its high expression is is associated with poor prognosis in hepatocellular carcinoma (HCC) patients. However, the mechanism of action of PCNA in HCC remains unclear. Herein, we showed that targeting PCNA genetically or pharmacologically suppressed DNA damage repair and induced cell cycle arrest in HCC cells. Mechanistically, poly (ADPribose) polymerase 1 (PARP1) was identified as a downstream target of PCNA and directly interacted with PCNA. Inhibiting the expression or activity of PCNA increased the sensitivity of HCC cells to the PARP1 inhibitor, Olaparib. In addition, AOH1160 and Olaparib synergistically inhibited the proliferation, DNA damage repair and cell cycle progression of HCC cells. These findings uncover the relationship between PCNA and PARP1 in regulating the malignant progression of HCC, and highlight the pivotal role of PCNA/PARP1 axis in DNA damage repair and cell cycle progression. The correlation between elevated PCNA levels and unfavorable prognosis underscores its potential as a therapeutic biomarker. Repression of PCNA/PARP1 axis significantly inhibits the malignant proliferation of HCC cells both in vitro and in vivo. Collectively, the study provides a mechanistic foundation for therapies targeting PCNA/PARP1 axis.