SIAH1 causes growth arrest and apoptosis in hepatoma cells through β-catenin degradation-dependent and -independent mechanisms

Abstract

Abstract.We have previously shown that expression of SIAH1 is frequently down-regulated in HCCs and associated with their advanced stages. It has been shown that SIAH1 functions in the phosphorylation-independent degradation of ß-catenin and induces apoptosis and growth arrest. To examine if the effects of SIAH1 overexpression depend on the altered ß-catenin signaling pathway, we transferred the SIAH1 gene into three hepatoma cell lines with different genetic backgrounds: HepG2 (mutant ß-catenin), SNU475 (mutant AXIN1), and Huh7 cells (wild type ß-catenin and AXIN1). SIAH1 significantly decreased aberrant ß-catenin signal in HepG2 and SNU475 cells and induced growth arrest and apoptosis. However, SIAH1 also induced apoptosis in Huh7 cells, which retained a normal membranous distribution pattern of ß-catenin. Immunoblotting study demonstrated that SIAH1 also reduces the amount of PEG10 protein, which is known to be frequently overexpressed in HCC and to promote cell proliferation. These data suggest that PEG10 is another target protein of SIAH1 to induce apoptosis in hepatoma cells. Our results should lead to a better understanding of the relationship between deregulation of ß-catenin signals and hepatocarcinogenesis. Further investigations into the mechanisms by which SIAH1 promotes apoptosis and suppresses cell growth should also allow for the discovery of new therapeutic strategies. IntroductionHepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. Epidemiological studies have revealed that major causes of HCC are exposure to carcinogens such as aflatoxin B1, cirrhosis of any etiology, or chronic infection to hepatitis B or C. Molecular approaches have disclosed involvement of several genetic alterations in hepatocellular carcinogenesis, including mutation of TP53, ß-catenin and AXIN1 (1-3). Among these, mutation of ß-catenin or AXIN1 has been shown to result in nuclear accumulation of ß-catenin protein. Accumulated ß-catenin is known to associate with the Tcf/Lef family of transcriptional factors thereby activating target genes, such as c-myc and cyclin D1. Immunohistochemical analysis revealed that ß-catenin is aberrantly accumulated in nearly 50% of HCCs (3,4), suggesting that alteration of the ß-catenin signaling pathway is one of the most common and major mechanisms of the development of HCC.We previously performed a fine deletion mapping of chromosome 16 to search for a novel tumor suppressor gene for HCC and identified SIAH1, which is located at a commonly deleted region 16q12.1 (5). Although we did not find any somatic mutation of SIAH1, its expression was markedly down-regulated, especially in cases harboring loss of heterozygosity (LOH) at the SIAH1 locus. Moreover, decreased expression of SIAH1 was associated with the advanced stage of HCCs, suggesting that inactivation of SIAH1 plays an important role in HCC progression (5). SIAH1 is a human homolog of the Drosophila seven in absentia (sina), required for formation of the R7 photoreceptor cells during eye developmen...

Siah: A Promising Anticancer Target

“…In other cancers, such as gastric and liver cancer, low levels of Siah1 have been shown to reduce apoptosis, thereby promoting cancer progression (25,26). Together these studies and those listed in Table 1 allude to a tumor-suppressive role for Siah1 proteins in various cancer types.…”

An Upregulation of SIAH1 After Spinal Cord Injury in Adult Rats

“…Moreover, following the spinal cord injury, the coexpression of SIAH1 and active caspase-3 were detected in our study. Previous studies have shown that enhanced expression of SIAH1 appeared to be linked with apoptotic signal (Yoshibayashi et al 2007;Wen et al 2010a,b). Overexpression of SIAH1 can induce apoptosis of neuronally differentiated PC12 cells in vitro (Xu et al 2006).…”

“…To date, several important targets of the SIAH1-dependent ubiquitin-proteasome pathway have been identified (Venables et al 2004;Hara et al 2005;Santelli et al 2005;Zhou et al 2008;Kim et al 2009). Increased expression of SIAH1 is observed to be associated with the onset of nontumorigenicy in revertant tumorigenic cell lines and with several apoptotic processes (Matsuo et al 2003;Okabe et al 2003;Yoshibayashi et al 2007;Wen et al 2010a,b). Besides, some reports showed that SIAH1 can trigger activation of the c-Jun NH2-kinase (JNK) signaling pathway (Xu et al 2006;Wen et al 2010a,b).…”

The ubiquitin–proteasome system and its potential application in hepatocellular carcinoma therapy

“…The reduced mRNA expression of SIAH1 was first reported to be significantly related with advanced HCCs, including the larger, poorly differentiated tumors, and the tumors in advanced stages [63]. SIAH1 causes growth arrest and apoptosis in HCC cells through β-catenin degradation-dependent and -independent mechanisms [64] or facilitating the p53-mediated HBx degradation [65]. After that, Malz and his colleagues found a reduction of cytoplasmic SIAH1 but an accumulation of nuclear SIAH1 in HCC tissues.…”