Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Dec;45(6):1187-1202.
doi: 10.1007/s13402-022-00709-1. Epub 2022 Nov 3.

DNASE1L3 inhibits hepatocellular carcinoma by delaying cell cycle progression through CDK2

Jiaqi Sun  1 , Xiyang Wang  1 , Qingsong Shen  1 , Min Wang  1 , Shuxian Chen  1 , Xuechun Zhang  1 , Yongping Huang  1 , Zhonglin Zhang  2 , Wenhua Li  1 , Yufeng Yuan  2 , Zan Huang  3
Affiliations

DNASE1L3 inhibits hepatocellular carcinoma by delaying cell cycle progression through CDK2

Jiaqi Sun et al. Cell Oncol (Dordr). 2022 Dec.

Abstract

Purpose: Dysregulated cell cycle targeting is a well-established therapeutic strategy against hepatocellular carcinoma (HCC). Dissecting the underlying mechanism may improve the efficacy of HCC therapy.

Methods: HCC data from TCGA and new clinical samples were used for DNASE1L3 expression analysis and for assessing its correlation with HCC development. The in vitro function of DNASE1L3 in HCC cell proliferation, colony formation, migration and invasion was assessed using RTCA, CCK-8 and transwell assays and the in vivo function in subcutaneous tumor formation in a xenograft nude mouse model. The role of DNASE1L3 in HCC tumorigenesis was further verified in AKT/NRASV12-induced and DEN/CCl4-induced primary liver cancers in wildtype and Dnase1l3-/- mice. Finally, RNA-Seq analysis followed by biochemical methods including cell cycle, immunofluorescence, co-immunoprecipitation and Western blotting assays were employed to reveal the underlying mechanism.

Results: We found that DNASE1L3 was significantly downregulated and served as a favorable prognostic factor in HCC. DNASE1L3 dramatically attenuated HCC cell proliferation, colony formation, migration and invasion in vitro and reduced subcutaneous tumor formation in nude mice in vivo. Furthermore, DNASE1L3 overexpression dampened AKT/NRASV12-induced mouse liver cancer in wildtype mice and DNASE1L3 deficiency worsened DEN/CCl4-induced liver cancer in Dnase1l3-/- mice. Systemic analysis revealed that DNASE1L3 impaired HCC cell cycle progression by interacting with CDK2 and inhibiting CDK2-stimulated E2F1 activity. C-terminal deletion (DNASE1L3ΔCT) diminished the interaction with CDK2 and abrogated the inhibitory function against HCC.

Conclusion: Our study unveils DNASE1L3 as a novel HCC cell cycle regulator and tumor suppressor. DNASE1L3 impairs HCC tumorigenesis by delaying cell cycle progression possibly through disrupting the positive E2F1-CDK2 regulatory loop. DNASE1L3 may serve as a target for the development of novel therapeutic strategies against HCC.

Keywords: CDK2; Cell cycle; DNASE1L3; Hepatocellular carcinoma.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Z. Chen, H. Xie, M. Hu, T. Huang, Y. Hu, N. Sang, Y. Zhao, Recent progress in treatment of hepatocellular carcinoma. Am. J. Cancer Res. 10, 2993–3036 (2020)
    1. T. Otto, P. Sicinski, Cell cycle proteins as promising targets in cancer therapy. Nat. Rev. Cancer 17, 93–115 (2017) - DOI
    1. A. Jindal, A. Thadi, K. Shailubhai, Hepatocellular Carcinoma: Etiology and Current and Future Drugs. J. Clin. Exp. Hepatol. 9, 221–232 (2019) - DOI
    1. X. Qing, W. Xu, J. Zong, X. Du, H. Peng, Y. Zhang, Emerging treatment modalities for systemic therapy in hepatocellular carcinoma. Biomark. Res 9, 64 (2021) - DOI
    1. M. Malumbres, M. Barbacid, Cell cycle, CDKs and cancer: a changing paradigm. Nat. Rev. Cancer 9, 153–166 (2009) - DOI

LinkOut - more resources