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Research Paper|Volume 13, Issue 15|pp 19317—19338

The deubiquitinase OTUD3 stabilizes ACTN4 to drive growth and metastasis of hepatocellular carcinoma

Peiyi Xie1, Yanglin Chen2, Hongfei Zhang3, Guichao Zhou4, Qing Chao5, Jiangwen Wang6, Yue Liu6, Jiayu Fang6, Jing Xie6, Jing Zhen6, Zhiyuan Wang7, Liang Hao8, Da Huang9
  • 1Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
  • 2Second Abdominal Surgery Department, Affiliated Tumor Hospital of Nanchang University, Nanchang, Jiangxi, China
  • 3School of Basic Medical Sciences, Medical College of Nanchang University, Nanchang, Jiangxi, China
  • 4Department of Orthopedics, The Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
  • 5Second College of Clinical Medicine, Zunyi Medical University, Zhuhai, Guangdong, China
  • 6Second College of Clinical Medicine, Nanchang University, Nanchang, Jiangxi, China
  • 7Department of Imaging Center, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
  • 8Department of Orthopedics, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
  • 9Department of Thyroid Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
* Equal contribution
Received: January 23, 2021Accepted: May 31, 2021Published: August 10, 2021
https://doi.org/10.18632/aging.203293

Copyright: © 2021 Xie et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

OTU domain-containing protein 3 (OTUD3), a deubiquitinating enzyme, has been shown to participate in progression of multiple malignancies. The accurate function of OTUD3 in hepatocellular carcinoma (HCC) progression remains elusive. We found that OTUD3 was significantly overexpressed in HCC, and higher OTUD3 expression was correlated with larger tumor size, more distant metastasis, and worse TNM stage. A series of gain- and loss-of-function assays were also performed to examine the oncogenic function of OTUD3 in promoting HCC cell growth and metastasis in vitro. Using a xenograft mouse model, we showed that OTUD3 accelerated HCC progression in vivo. Furthermore, alpha-actinin 4 (ACTN4) was identified as a downstream target of OTUD3 through mass spectrometry analysis, and the ACTN4 protein level was significantly related to OTUD3 expression. Additionally, OTUD3 directly bound with ACTN4 and deubiquitinated ACTN4 to stabilize it. Finally, ACTN4 was found to be essential for OTUD3-mediated HCC proliferation and metastasis in vitro and in vivo. Collectively, our findings identify the oncogenic role of OTUD3 in HCC and suggest that OTUD3 can be considered as a pivotal prognostic biomarker and a potential therapeutic target.