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

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

doi:10.1186/s12935-020-1124-3

Abstract

BackgroundColorectal 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.MethodsTo 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.ResultsWe 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.ConclusionsThese findings suggested that Siah1 is a novel potential prognostic biomarker and plays a tumor suppressor role in the development and progression of CRC.

Highlights

Colorectal cancer (CRC) is one of the most common malignant tumors in the world
Siah E3 ubiquitin protein ligase 1 (Siah1) is downregulated in CRC tissues, and its expression was associated is progression and poor prognosis in CRCWestern blot was used to detect the expression of Siah1 in 10 CRC tissues
To analyze the relationship between the expression of Siah1 and the clinicopathological parameters, the expression of Siah1 protein was detected by immunohistochemistry (IHC) in 170 paraffin-embedded archived CRC tissues

Summary

Introduction

Siah E3 ubiquitin protein ligase 1 (Siah1) has been identified as a tumor suppressor gene and plays an important role in the develop‐ ment of malignant tumors. It is known that many oncogenes and tumor suppressor genes are involved in the development of CRC, such as Kirsten rat sarcoma viral oncogene homolog (KRAS) [1], β-catenin, Xiao et al Cancer Cell Int (2020) 20:50 adenomatous polyposis coli (APC) [2], tumor protein p53 (TP53) and so on [3, 4]. Ubiquitination plays an important role in the development of colorectal cancer It regulates cellular biological processes through the ubiquitin critical proteins. Siah can bind to a variety of target proteins, thereby triggering their ubiquitylation and degradation by the ubiquitin–proteasome pathway. These target proteins include NcoR (nuclear receptor co-repressor), TRAF (TNF receptor associated factor), β-catenin, c-Myb (c-MYB proto-oncogene), APC, Kid and so on [5,6,7,8]

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