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

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.

Siah1 in cancer and nervous system diseases (Review)

“…The knock down of Siah1 by shRNA promotes HCT116/SW480 CRC cell proliferation and migration, and results in fast tumor growth and a markedly large tumor volume in nude mice. Mechanically, Siah1 represses the occurrence and development of CRC by promoting the ubiquitylation of AKT and inhibiting the activity of the MAPK, PI3K-AKT and Hippo pathways (108). Additionally, the mutations of p53 in pancreatic cancer act in the opposite manner to the wild-type p53, inhibiting the transcription of Siah1 and leading to the accumulation of the oncoprotein.…”

SIAH1 reverses chemoresistance in epithelial ovarian cancer via ubiquitination of YBX-1

“…Emerging a growing number of studies have shifted the focus to the effect of SIAH1 on cancers recently [ 30 , 32 , 33 ]. For example, SIAH1 exerts inhibitory effects on the progression and development of many kinds of malignant tumors, including colorectal cancer, hepatocellular carcinogenesis, breast cancer, and prostate cancer [ 29 , 33 , 34 ], and the ubiquitin ligase activity of SIAH1 largely contributes to its tumor-inhibiting effect. Data from The Cancer Genome Atlas (TCGA) show that SIAH1 gene downregulation is a common genetic alteration in different kinds of cancers.…”

SIAH1-mediated RPS3 ubiquitination contributes to chemosensitivity in epithelial ovarian cancer

“…SIAH1 reportedly behaves as a tumour suppressor during tumourigenesis by binding to numerous proteins, such as NcoR, TRAF, β-catenin, c-Myb, APC, and Kid, and thereby triggers their ubiquitylation and degradation via the ubiquitinproteasome pathway [9][10][11][12]. In addition, SIAH1 has been implicated in cancer-related signalling pathways, including cell apoptosis (β-catenin, Sec6) [13,14], DNA damage repair (c-Abl, HIPK2, and TRF2) [15][16][17] and the in vivo hypoxia response (PHD3, HIF-1a, and IL-17) [13,18,19]. Thus, SIAH1 has been proposed as a promising therapeutic target in cancer treatment [20].…”