The ternary complex factor Net/Elk-3 participates in the transcriptional response to hypoxia and regulates HIF-1α

Groß, Christian; Dubois-Pot, Hélène; Wasylyk, Bohdan

doi:10.1038/sj.onc.1210736

Cited by 38 publications

(44 citation statements)

References 23 publications

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“…Previous studies demonstrated that ELK3 participates in the regulation of various genes, including c-fos, egr-1, and PAI-1. In addition, ELK3 is known as a regulator of HIF-1α expression by modulating HIF-1α stability (21)(22)(23)30,31). HIF-1α plays a key role in the induction of cancer invasion, metastasis and angiogenesis, as well as in cancer growth, glucose metabolism, and other metastasis-associated signaling pathways (32)(33)(34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

“…These observations suggest that EMT may play an important role in HCC metastasis. Moreover, recent studies revealed that ELK3 is associated with the regulation of hypoxia-induced factor 1α (HIF-1α) (30,31). HIF-1α is a transcription factor that plays a well-established role in cancer development, progression and metastasis.…”

Section: Elk3 Promotes the Migration And Invasion Of Liver Cancer Stementioning

confidence: 99%

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ELK3 promotes the migration and invasion of liver cancer stem cells by targeting HIF-1α

et al. 2016

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Abstract. Hepatocellular carcinoma (HCC) is the fifth most common solid cancer and the third most common cause of cancer-related mortality. HCC develops via a multistep process associated with genetic aberrations that facilitate HCC invasion and migration and promote metastasis. A growing body of evidence indicates that cancer stem cells (CSCs) are responsible for tumorigenesis, cancer cell invasion and metastasis. Despite the extremely small proportion of cancer cells represented by this subpopulation of HCC cells, CSCs play a key role in cancer metastasis and poor prognosis. ELK3 (Net/SAP-2/Erp) is a transcription factor that is activated by the Ras/extracellular signal-regulated kinase (ERK) signaling pathway. It plays several important roles in various physiological processes, including cell migration, invasion, wound healing, angiogenesis and tumorigenesis. In the present study, we investigated the role of ELK3 in cancer cell invasion and metastasis in CD133 + /CD44 + liver cancer stem cells (LCSCs). We isolated LCSCs expressing CD133 and CD44 from Huh7 HCC cells and evaluated their metastatic potential using invasion and migration assays. We found that CD133 + /CD44 + cells had increased metastatic potential compared with non-CD133 + /CD44 + cells. We also demonstrated that ELK3 expression was upregulated in CD133 + /CD44 + cells and that this aberration enhanced cell migration and invasion. In addition, we identified the molecular mechanism by which ELK3 promotes cancer cell migration and invasion. We found that silencing of ELK3 expression in CD133 + /CD44 + LCSCs attenuated their metastatic potential by modulating the expression of heat shock-induced factor-1α (HIF-1α). Collectively, the results of the present study demonstrated that ELK3 overexpression promoted metastasis in CD133 + /CD44 + cells by regulating HIF-1α expression and that silencing of ELK3 expression attenuated the metastatic potential of CD133 + /CD44 + LCSCs. In conclusion, modulation of ELK3 expression may represent a novel therapeutic strategy for preventing HCC metastasis and invasion.

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Section: Discussionmentioning

confidence: 99%

Section: Elk3 Promotes the Migration And Invasion Of Liver Cancer Stementioning

confidence: 99%

ELK3 promotes the migration and invasion of liver cancer stem cells by targeting HIF-1α

et al. 2016

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“…Under hypoxia, Hif1a hydroxylation decreases due to reduced PHD abundance and activity (8). We and others have shown that Siah proteins polyubiquitinate PHDs under hypoxic conditions (9,10), thereby targeting them for proteasomal degradation and allowing unmodified Hif-1a protein to dimerize with Hif-1b. The role of Siah proteins in tumor progression is becoming clearer (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Vascular Normalization by Loss of Siah2 Results in Increased Chemotherapeutic Efficacy

et al. 2012

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Tumor hypoxia is associated with resistance to antiangiogenic therapy and poor prognosis. The Siah E3 ubiquitin ligases regulate the hypoxic response pathway by modulating the turnover of the master proangiogenic transcription factor hypoxia-inducible factor-1a . In this study, we show that genetic deficiency in the Siah family member Siah2 results in vascular normalization and delayed tumor growth in an established transgenic model of aggressive breast cancer. Tumors arising in a Siah2À/À genetic background showed increased perfusion and pericyte-associated vasculature, similar to that occurring with antiangiogenic therapy. In support of the role of Siah2 in regulating levels of Hif-1a, expression of angiogenic factors was decreased in Siah2tumors. Blood vessel normalization in Siah2 À/À tumors resulted in an increased response to chemotherapy and prolonged survival. Together, our findings offer a preclinical proof of concept that targeting Siah2 is sufficient to attenuate Hif-1a-mediated angiogenesis and hypoxia signaling, thereby improving responses to chemotherapy.

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“…The contributions of SRF and its cofactors to EC function are poorly understood. In cultured ECs, ELK3 participates in transcriptional responses to hypoxia by regulation of HIF-1α protein stability (28,29). In vitro cultured ECs revealed a role for SRF in VEGF-mediated angiogenesis, actin polymerization, and EC migration (30).…”

Section: Introductionmentioning

confidence: 99%

Endothelial SRF/MRTF ablation causes vascular disease phenotypes in murine retinae

Weinl¹,

Riehle²,

Park³

et al. 2013

J. Clin. Invest.

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Retinal vessel homeostasis ensures normal ocular functions. Consequently, retinal hypovascularization and neovascularization, causing a lack and an excess of vessels, respectively, are hallmarks of human retinal pathology. We provide evidence that EC-specific genetic ablation of either the transcription factor SRF or its cofactors MRTF-A and MRTF-B, but not the SRF cofactors ELK1 or ELK4, cause retinal hypovascularization in the postnatal mouse eye. Inducible, EC-specific deficiency of SRF or MRTF-A/MRTF-B during postnatal angiogenesis impaired endothelial tip cell filopodia protrusion, resulting in incomplete formation of the retinal primary vascular plexus, absence of the deep plexi, and persistence of hyaloid vessels. All of these features are typical of human hypovascularization-related vitreoretinopathies, such as familial exudative vitreoretinopathies including Norrie disease. In contrast, conditional EC deletion of Srf in adult murine vessels elicited intraretinal neovascularization that was reminiscent of the age-related human pathologies retinal angiomatous proliferation and macular telangiectasia. These results indicate that angiogenic homeostasis is ensured by differential stage-specific functions of SRF target gene products in the developing versus the mature retinal vasculature and suggest that the actin-directed MRTF-SRF signaling axis could serve as a therapeutic target in the treatment of human vascular retinal diseases.

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The ternary complex factor Net/Elk-3 participates in the transcriptional response to hypoxia and regulates HIF-1α

Cited by 38 publications

References 23 publications

ELK3 promotes the migration and invasion of liver cancer stem cells by targeting HIF-1α

ELK3 promotes the migration and invasion of liver cancer stem cells by targeting HIF-1α

Vascular Normalization by Loss of Siah2 Results in Increased Chemotherapeutic Efficacy

Endothelial SRF/MRTF ablation causes vascular disease phenotypes in murine retinae

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