Downregulation of Siah1 promotes colorectal cancer cell proliferation and migration by regulating AKT and YAP ubiquitylation and proteasome degradation

Zhiyuan Xiao; Zhigang Wei; Danling Deng; Zhe Zheng; Yali Zhao; Shenglu Jiang; Dan Zhang; Ling-Jie Zhang; Mingmei Fan; Siqi Chen; ShuYang Wang; Yanqing Ding; Yaping Ye; Hongli Jiao

doi:10.1186/s12935-020-1124-3

Downregulation of Siah1 promotes colorectal cancer cell proliferation and migration by regulating AKT and YAP ubiquitylation and proteasome degradation

Cancer Cell Int. 2020 Feb 13:20:50. doi: 10.1186/s12935-020-1124-3. eCollection 2020.

Authors

Zhiyuan Xiao^#^{1

2

3}, Zhigang Wei^#⁴, Danling Deng^#^{1

2

5}, Zhe Zheng^{1

2}, Yali Zhao^{1

2}, Shenglu Jiang^{1

2}, Dan Zhang^{1

2}, Ling-Jie Zhang^{1

2}, Mingmei Fan^{1

2}, Siqi Chen^{1

2}, ShuYang Wang^{1

2}, Yanqing Ding^{1

2}, Yaping Ye^{1

2}, Hongli Jiao^{1

2}

Affiliations

¹ 1Department of Pathology, Nanfang Hospital and School of Basic Medical Science, Southern Medical University, Guangzhou, 510515 China.
² 2Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China.
³ 3Department of Pathology, Shenzhen People's Hospital, Second Clinical Medical College of Jinan University, Shenzhen, Guangdong China.
⁴ 4Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
⁵ Department of Pathology, Shaoyang Central Hospital, Affiliated Shaoyang Hospital of University of South China, Shaoyang, Hunan China.

^# Contributed equally.

Abstract

Background: Colorectal cancer (CRC) is one of the most common malignant tumors in the world. Siah E3 ubiquitin protein ligase 1 (Siah1) has been identified as a tumor suppressor gene and plays an important role in the development of malignant tumors. However, the potential role and molecular mechanism of Siah1 in the development and progression of CRC is still unclear.

Methods: To explore the role and molecular mechanism of Siah1 in the development and progression of CRC, we examined the expression of Siah1 in CRC tissue samples and analyzed its association with progression and prognosis in CRC. In addition, overexpression and knockdown of Siah1 was used to investigate its activity in CRC cells. We also use bioinformatics to analyze and verify the significant roles of Siah1 in critical signaling pathways of CRC.

Results: We found that the expression of Siah1 was significantly downregulated in CRC tissues, and low expression of Siah1 was associated with aggressive TNM staging and poor survival of CRC patients. Moreover, we revealed that overexpression of Siah1 in CRC cells markedly inhibited CRC cell proliferation and invasion in vitro and in vivo, while knockdown of Siah1 enhanced CRC cell proliferation and invasion. Furthermore, we found that Siah1 prohibited cell proliferation and invasion in CRC partially through promoting AKT (the serine-threonine protein kinase) and YAP (yes associated protein) ubiquitylation and proteasome degradation to regulate the activity of MAPK(mitogen-activated protein kinase 1), PI3K-AKT (phosphatidylinositol 3-kinase-the serine-threonine protein kinase) and Hippo signaling pathways.

Conclusions: These findings suggested that Siah1 is a novel potential prognostic biomarker and plays a tumor suppressor role in the development and progression of CRC.

Keywords: Colorectal cancer; Migration; Proliferation; Siah1; Ubiquitylation.