Nuclear accumulation of seven in absentia homologue‐2 supports motility and proliferation of liver cancer cells

Abstract

Stability of many tumor-relevant proteins is partly mediated by E3 ligases, which determine substrate specificity within the ubiquitin system. Recent data demonstrated that increased nuclear expression of the E3 ligase seven in absentia homologue (SIAH)-1 in human hepatocarcinogenesis supports tumor cell proliferation and migration. To define whether closely related SIAH-2 synergizes with protumorigenic SIAH-1, we systematically analyzed expression, localization and functional relevance of SIAH-2 in human hepatocellular carcinoma (HCC). Nuclear accumulation of SIAH-2 is detectable in more than 60% of all HCCs and correlates with tumor progression, cell proliferation and distant metastasis. An inverse correlation between nuclear SIAH-1 and SIAH-2 was detected, suggesting independent mechanisms for nuclear enrichment. Inhibition of nuclear SIAH-2 by RNAi in HCC cell lines reduced proliferation as well as lateral tumor cell motility and transmigration; however, combined knock down of both SIAH-1 and SIAH-2 did not further amplify biological effects compared to single gene inhibition. Reduction of SIAH-2 expression sensitizes HCC cells to the treatment with different cytostatic drugs, demonstrating that SIAH-2-targeting approaches may increase the response of HCC cells to conventional chemotherapy. Together, these data show that SIAH-2-as described for SIAH-1-accumulates in nuclei of HCC cells where it supports tumor growth and tumor cell dissemination. Because the nuclear pattern of SIAH-2 differs in HCC tissues from the SIAH-1 pattern and because the inactivation of SIAH-2 is not compensated by SIAH-1, the specific inhibition of SIAH-2 (especially in combination with other drugs) represents a promising therapeutic strategy for HCC.The ubiquitin-proteasome system controls bioactivity, localization and protein turnover based on the sequential impact of E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes and E3 ubiquitin-protein ligases.1 Substrate proteins are subjected to ubiquitination associated with different fates of the targeted protein; in case of polyubiquitination, targets are mostly degraded, while in the case of monoubiquitination, substrate activity or subcellular localization is affected.2 Consequently, the ubiquitin-conjugating system regulates different cellular processes such as mitosis, apoptosis and genomic integrity under physiological and pathophysiological conditions.In human carcinogenesis, accumulation of oncogenes (e.g., c-MYC) and ablation of tumor suppressors (e.g., p53) are frequently influenced by the bioactivity of E3 ligases. This family of more than 600 members contains specific ligase proteins (e.g., BRCA1) as well as multisubunit ligases (e.g., SCF-Skp2), which, together with respective E2 conjugating factors, define substrate specificity. 3 In addition, recent data demonstrated that the proteasome system improves cell vitality in the presence of aneuploidy, which is a key characteristic of many solid tumors. 4 Because dysfunction of the ubiquitin-proteasome system affe...

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

“…Nuclear accumulation of SIAH1 supports different pro-tumorigenic processes in human hepatocarcinogenesis in vitro, and promotes HCC cell proliferation by partly employing the transcription factor FBP3 (far-upstream element binding protein 3) [66]. The nuclear accumulation of SIAH2 is also detectable in most HCCs and correlates with tumor progression, and reduction of the SIAH2 expression increases the response of HCC cells to different cytostatic drugs, representing a promising therapeutic strategy for HCC [67].…”

Siah: A Promising Anticancer Target

“…These findings are reflected by increased correlation of Siah2 with high-grade, malignant human prostate cancers but not low-grade tumors (17). Furthermore, in patients with hepatocellular carcinoma (HCC), nuclear accumulation of Siah1 and Siah2 were correlated with hepatocarcinogenesis and tumor dedifferentiation (21,22). Together, these reports describe oncogenic functions for Siah proteins, especially Siah2, in breast, prostate, and liver cancer and highlight an association between increased Siah2 levels and more malignant and invasive stages of cancer.…”

“…Recently, one study in HCC reported that nuclear protein accumulation of Siah1 and Siah2 were weakly and inversely correlated, suggesting potentially exclusive expression patterns (22). This has so far been the only study to address what happens to the second Siah protein in the same cancer or cohort.…”

Investigating the Molecular Basis of Siah1 and Siah2 E3 Ubiquitin Ligase Substrate Specificity

“…In contrast to the role of Siah1, Siah2 has been described to function as a proto-oncogene. Growing evidence highlights the functional role of Siah2 in promoting the progression of multiple types of cancer, including breast [25]–[27], lung [28], pancreatic [29], prostate [30], [31], liver [32] cancer and melanoma [13].…”