2. Academic Validation
  3. HBV core protein enhances WDR46 stabilization to upregulate NUSAP1 and promote HCC progression

HBV core protein enhances WDR46 stabilization to upregulate NUSAP1 and promote HCC progression

  • Hepatol Commun. 2025 May 6;9(5):e0680. doi: 10.1097/HC9.0000000000000680.
Fanyun Kong 1,  Ensi Bao 1,  Yujie Zhong 1,  Yuxin Wang 1,  Ruyu Liu 2,  Huanyang Zhang 1,  Lu Yang 1,  Rong Jiang 1,  Xuanke Liu 1,  Chen Li 1,  Xiangye Liu 1,  Xiucheng Pan 3,  Kuiyang Zheng 1 4,  Hongjuan You 1,  Renxian Tang 1 4
Affiliations

Affiliations

  • 1 Department of Pathogenic Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 2 Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
  • 3 Department of Infectious Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
  • 4 National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, China.
PMID: 40366140 DOI: 10.1097/HC9.0000000000000680
Abstract

Background: The HBV core protein (HBC) is crucial for the progression of HCC. WD repeat-containing (WDR) 46 (WDR46) is implicated in the development of different tumors. Nevertheless, whether WDR46 is controlled by HBC to drive hepatocarcinogenesis remains unclear.

Methods: Different HCC cohorts, immunohistochemical staining, and bioinformatics analysis were utilized to estimate the clinical correlation between WDR46 and HBV-associated HCC. Western blotting, co-immunoprecipitation, chromatin immunoprecipitation, and oncology functional assays were performed to evaluate the effect of HBC on WDR46 in upregulating nucleolar spindle-associated protein 1 (NUSAP1), the influence of WDR46 on HBC-mediated HCC cell biological functions, and the mechanisms of WDR46 upregulation mediated by HBC to increase NUSAP1.

Results: WDR46 expression was elevated in HBV-related HCC in a HBC-dependent manner. Overexpression of WDR46 is closely linked to severe prognosis of tumors. Functionally, WDR46 contributes to HBC-induced cell growth and migration in vitro and in vivo. Furthermore, HBC enhanced WDR46 protein stabilization by hampering the interaction between WDR46 and TRIM25, thereby decreasing WDR46 ubiquitination. NUSAP1, a DNA replication-related molecule, is a vital downstream target of WDR46. Relying on WDR46, HBC promoted NUSAP1 upregulation to modulate the biological functions of HBC in HCC cells. Importantly, HBC enhanced the interaction between WDR46 and the transcription factor c-Myc to facilitate c-Myc recruitment to the NUSAP1 promoter, leading to the increase of NUSAP1 transcription.

Conclusions: Our comprehensive data provides new insights into the mechanisms responsible for HBC-induced hepatocarcinogenesis. WDR46 and its downstream molecule, NUSAP1, may act as novel therapeutic targets for HBV-related tumors.

Keywords

HBV core protein; NUSAP1; TRIM25; WDR46; c-Myc.

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