Effect of Disrupting Seven-in-Absentia Homolog 2 Function on Lung Cancer Cell Growth

Ahmed, Atique U.; Schmidt, Rebecca L.; Park, Cheol Hong; Reed, Nanette R.; Hesse, Shayla; Thomas, Charles F.; Molina, Julian R.; Deschamps, Claude; Yang, Ping; Aubry, Marie Christine; Tang, Amy

doi:10.1093/jnci/djn365

Cited by 68 publications

(101 citation statements)

References 58 publications

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“…Upon these findings, we speculate that downstream factors of Siah1 other than HIF1α may affect tumour progression. Siah was initially identified as a tumour suppressor gene [12], although recent studies have shown that knock-down of Siah by shRNA could significantly impede lung and pancreatic tumour growth in vitro and in vivo, indicating that expression of Siah itself promotes tumour growth [9,13,23]. Another study in breast cancer also showed that increased Siah expression was related to the aggressiveness of breast cancers [24].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, understanding the molecular mechanisms that regulate Siah expression will likely provide new insights into the pivotal function of Siah in cancer biology and should contribute to novel anti-cancer strategies [12,13,25]. The relationship between Siah1 and HIF1α expression and patient prognosis was examined by Kaplan-Meier analysis.…”

Section: Discussionmentioning

confidence: 99%

“…Siah-family proteins are the human homologues of seven-in-absentia, a conserved RING finger E3 ubiquitin ligase and essential downstream component of the Drosophila Ras signaling pathway. Two homologues, Siah1 and Siah2, have been shown to be involved in the response to DNA damage, the hypoxic response, inflammation, and several oncogenic signals including those propagated by Ras and epidermal growth factor receptor (EGFR) [10][11][12][13]. To date, few studies have addressed the role of Siah expression in cancer, and there has been no consensus as to the biologic significance of such expression [14,15].…”

Section: Introductionmentioning

confidence: 99%

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Expression of seven-in-absentia homologue 1 and hypoxia-inducible factor 1 alpha: Novel prognostic factors of nasopharyngeal carcinoma

et al. 2013

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(T. Yoshizaki). Keywords:seven-in-absentia homologue 1 (Siah1) hypoxia-inducible factor 1 alpha (HIF1α) latent membrane protein 1 (LMP1) Epstein-Barr virus (EBV) nasopharyngeal carcinoma ABSTRACT Nasopharyngeal carcinoma (NPC) is an EBV-associated cancer. We analysed Siah1 expression as well as LMP1 and HIF1α expression by immuno-histochemical staining in 74 NPC biopsy specimens and found that the expression of Siah1 was significantly correlated with advanced tumour status and stage. Moreover, Siah1-positive and HIF1α-positive cases had significantly worse prognoses. The expression score for LMP1 was remarkably correlated with that of Siah1, whereas there was little correlation between LMP1 expression and the other markers evaluated. This is the first study to evaluate the pattern and clinical significance of Siah1 and HIF1α expression in NPC, and such an evaluation is valuable for identifying those patients at a high risk for a poor prognosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Expression of seven-in-absentia homologue 1 and hypoxia-inducible factor 1 alpha: Novel prognostic factors of nasopharyngeal carcinoma

et al. 2013

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“…Finally, in other cancers, such as liver and gastric cancers, low levels of Siah1 expression promoted cancer progression [31] . A dominant negative Siah protein was also found to inhibit ERK signaling and cell proliferation, increase apoptosis induction, and reduce tumorigenesis of A549 human lung cancer cells, when injected into nude mice [32] . In addition, inhibition of the expression of Siah had an anti-tumorigenic effect in mouse melanoma, SW1 cells, and breast cancer cells [33] .…”

Section: Function Of Siah As a Tumor Sup-pressor Protein And Its Rolementioning

confidence: 98%

Novel Function of E3 Ubiquitin Ligase Siah2 to Regulate ROS Metabolism

Baba¹,

Miyazaki²

2016

Journal of Biochemistry and Molecular Biology Research

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The seven in absentia homolog (Siah) family proteins are components of E3 ubiquitin ligase complexes that catalyze the ubiquitination of proteins. Siah proteins target their substrates for proteasomal degradation. Several studies have reported that Siah proteins are involved in tumorigenesis and angiogenesis, particularly through the Ras and HIF-1a signaling pathways in hypoxic response. Recent studies also have reported that Siah2 stabilization impairs the NF-E2-related factor 2 (Nrf2) signaling pathway, which is a master regulator of reactive oxygen species (ROS) metabolism. Hypoxia induces the phosphorylation of Nrf2 and then decreases the Keap1-mediated degradation of Nrf2 compared with that under normoxia. In addition, hypoxia-induced Siah2 provides a dominating Nrf2 degradation pathway over that of Keap1 under hypoxia. Given their critical roles in ROS metabolism, Siah proteins are attractive targets for effective therapy under particular conditions such as hypoxia and hypoglycemia.

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“…The role of Siah2 in tumor development has been extensively studied. Inhibition of Siah reportedly attenuates breast, pancreatic, lung, prostate, and melanoma tumors (13)(14)(15)(16). Mechanistically, Siah2 contributes to tumor development and metastasis via its control of diverse substrates, as shown in a melanoma model (14).…”

mentioning

confidence: 99%

USP13 Enzyme Regulates Siah2 Ligase Stability and Activity via Noncatalytic Ubiquitin-binding Domains

Scortegagna

Subtil

et al. 2011

Journal of Biological Chemistry

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The RING finger E3 ubiquitin ligase Siah2 is implicated in control of diverse cellular biological events, including MAPK signaling and hypoxia. Here we demonstrate that Siah2 is subject to regulation by the deubiquitinating enzyme USP13. Overexpression of USP13 increases Siah2 stability by attenuating its autodegradation. Consequently, the ability of Siah2 to target its substrates prolyl hydroxylase 3 and Spry2 (Sprouty2) for ubiquitin-mediated proteasomal degradation is attenuated. Conversely, inhibition of USP13 expression with corresponding shRNA decreases the stability of both Siah2 and its substrate Spry2. Thus, USP13 limits Siah2 autodegradation and its ubiquitin ligase activity against its target substrates. Strikingly, the effect of USP13 on Siah2 is not mediated by its isopeptidase activity: mutations in its ubiquitin-binding sequences positioned within the ubiquitin-specific processing protease and ubiquitin-binding domains, but not within putative catalytic sites, abolish USP13 binding to and effect on Siah2 autodegradation and targeted ubiquitination. Notably, USP13 expression is attenuated in melanoma cells maintained under hypoxia, thereby relieving Siah2 inhibition and increasing its activity under low oxygen levels. Significantly, on melanoma tissue microarray, high nuclear expression of USP13 coincided with high nuclear expression of Siah2. Overall, this study identifies a new layer of Siah2 regulation mediated by USP13 binding to ubiquitinated Siah2 protein with a concomitant inhibitory effect on its activity under normoxia.Siah proteins are RING finger E3 ubiquitin ligases implicated in the ubiquitination and proteasome-dependent degradation of substrate molecules, which also limit their own availability through self-ubiquitination and degradation (1-3). Siah was first identified in Drosophila melanogaster as seven in absentia (sina), which regulates formation of the R7 photoreceptor through control of tramtrack stability (4, 5). Three murine Siah genes (Siah1a, Siah1b, and Siah2) share significant homology with the two human (SIAH1 and SIAH2) orthologues (6, 7).Siah2 is an important regulator of pathways activated under stress and hypoxia. Among substrates reportedly regulated by Siah under these conditions are TRAF2, ␣-ketoglutarate dehydrogenase, Spry2 (Sprouty2), and two of the three prolyl hydroxylases (8 -10). Given the role of PHD proteins as oxygen sensors and regulators of HIF1␣, the master transcription factor responding to hypoxia, Siah is implicated in the control of hypoxia, particularly within the range of 2-6% oxygen at which PHD proteins retain sufficient activity (11,12). The role of Siah2 in tumor development has been extensively studied. Inhibition of Siah reportedly attenuates breast, pancreatic, lung, prostate, and melanoma tumors (13-16). Mechanistically, Siah2 contributes to tumor development and metastasis via its control of diverse substrates, as shown in a melanoma model (14).A search for novel Siah2 interacting factors led to identification of the isopeptidase USP13 ...

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Effect of Disrupting Seven-in-Absentia Homolog 2 Function on Lung Cancer Cell Growth

Abstract: SIAH-2 may be a viable target for novel anti-RAS and anticancer agents aimed at inhibiting EGFR and/or RAS-mediated tumorigenesis.

Cited by 68 publications

References 58 publications

Expression of seven-in-absentia homologue 1 and hypoxia-inducible factor 1 alpha: Novel prognostic factors of nasopharyngeal carcinoma

Expression of seven-in-absentia homologue 1 and hypoxia-inducible factor 1 alpha: Novel prognostic factors of nasopharyngeal carcinoma

Novel Function of E3 Ubiquitin Ligase Siah2 to Regulate ROS Metabolism

USP13 Enzyme Regulates Siah2 Ligase Stability and Activity via Noncatalytic Ubiquitin-binding Domains

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