Cathepsin K promotes the proliferation of hepatocellular carcinoma cells through induction of SIAH1 ubiquitination and degradation

Chengming Zhang; Zhiyi Liu; Xiaotian Wang; Bin Zhang; Licheng Cui; Qinghe Hu; Bin Hu; Kuan Cao; Wengang Shan; Hengliang Shi; Renhao Wang

doi:10.1016/j.isci.2023.106852

Cathepsin K promotes the proliferation of hepatocellular carcinoma cells through induction of SIAH1 ubiquitination and degradation

iScience. 2023 May 9;26(6):106852. doi: 10.1016/j.isci.2023.106852. eCollection 2023 Jun 16.

Authors

Chengming Zhang^{1

2

3}, Zhiyi Liu^{1

2

3}, Xiaotian Wang^{1

2

3}, Bin Zhang^{1

2

3}, Licheng Cui^{1

2

3}, Qinghe Hu^{1

2

3}, Bin Hu^{1

2

3}, Kuan Cao^{1

2

3}, Wengang Shan^{1

2

3}, Hengliang Shi^{1

2

3

4}, Renhao Wang^{1

2

3}

Affiliations

¹ Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.
² Research Center of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
³ Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
⁴ Central Laboratory, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.

Abstract

Seven in absentia homolog 1 (SIAH1) was reported to be downregulated in hepatocellular carcinoma (HCC) and played an important role in HCC progression; however, the underlying reason remains unknown. Here, we found that Cathepsin K (CTSK), a protein potentially interacting with SIAH1, inhibits SIAH1 protein level. CTSK was highly expressed in HCC tissues. CTSK inhibition or downregulation suppressed HCC cell proliferation, whereas CTSK overexpression had the opposite effect; it promotes HCC cell proliferation by regulating the SIAH1/protein kinase B (AKT) pathway, wherein promotes SIAH1 ubiquitination. Neural precursor cells expressing developmentally downregulated 4 (NEDD4) was found to be a potential upstream ubiquitin ligase of SIAH1. Further, CTSK could mediate SIAH1 ubiquitination and degradation by increasing SIAH1 autoubiquitination and recruiting NEDD4 to ubiquitinate SIAH1. Finally, the roles of CTSK were confirmed in a xenograft mouse model. In conclusion, oncogenic CTSK was upregulated in human HCC tissues and accelerated HCC cell proliferation by downregulating SIAH1.

Keywords: Cancer; Cell biology; Molecular biology.