Potential role of WSB1 isoforms in growth and survival of neuroblastoma cells

Shichrur, Keren; Feinberg-Gorenshtein, Galina; Luria, Drorit; Ash, Susan; Yaniv, Isaac; Avigad, Smadar

doi:10.1038/pr.2014.2

Cited by 10 publications

(15 citation statements)

References 17 publications

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“…A gene expression analysis of 37 neuroblastoma patients revealed that increased WSB1 copy number correlates with good prognosis (28). In contrast, reduced cell proliferation and enhanced resistance to apoptosis are observed in both pancreatic cancer cells and neuroblastoma cells after WSB1 overexpression (16,29). More recently, data from hepatocellular carcinoma cells further suggest that WSB1 plays a critical role in hypoxia-induced chemoresistance (26).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Induced WSB1 Promotes the Metastatic Potential of Osteosarcoma Cells

et al. 2015

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Intratumoral hypoxia occurs in many solid tumors, where it is associated with the development of metastatic character. However, the connections between these phenomena are not fully understood. In this study, we define an integrative role for the E3 ubiquitin ligase subunit WSB1. In primary osteosarcomas, increased levels of WSB1 correlated with pulmonary metastatic potential. RNAi-mediated attenuation of WSB1 or disruption of its E3 ligase activity potently suppressed tumor metastasis. Quantitative proteomic and functional analyses revealed that WSB1 ubiquitylates the Rho-binding protein RhoGDI2 and promotes its proteasomal degradation, thereby activating Rac1 to stimulate tumor cell motility and invasion. Our findings show how WSB1 regulates key steps of the metastatic cascade in hypoxia-driven osteosarcoma, and they highlight a candidate therapeutic target to potentially improve the survival of patients with metastatic disease. Cancer Res; 75(22); 4839-51. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 99%

Hypoxia-Induced WSB1 Promotes the Metastatic Potential of Osteosarcoma Cells

et al. 2015

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“…And so far there is no report about the role of miRNAs in the expression of WSB1. Given that HIF-1α has been shown to up-regulate WSB1 in HCC combined with the evidence of WSB1 stabilizing HIF-1α [8, 9], there could be a positive feedback loop self-perpetuating the signaling between HIF-1α and WSB1. Because miR-529 presents as the sole upstream regulator of WSB1, it will be possible that mir-592 is a potential key regulator keeping the equilibrium of WSB1/HIF-1α signaling.…”

Section: Discussionmentioning

confidence: 99%

“…However, it remains poorly understood about the role of miRNAs in HIF-1α-altered tumor cell metabolism. WD repeat and SOCS box containing 1 (WSB1) was recently identified as a new member of the suppressor of cytokine signaling (SOCS) box protein family, and its expression was upregulated in multiple types of human cancers [8]. More recent evidence suggested that WSB1 is a direct target of HIF-1α in a human HCC model [9].…”

Section: Introductionmentioning

confidence: 99%

miR-592/WSB1/HIF-1α axis inhibits glycolytic metabolism to decrease hepatocellular carcinoma growth

Jia

Zhao

et al. 2016

Oncotarget

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Hepatocellular carcinoma (HCC) cells rapidly switch their energy source from oxidative phosphorylation to glycolytic metabolism in order to efficiently proliferate. However, the molecular mechanisms responsible for this switch remain unclear. In this study, we found that miR-592 was frequently downregulated in human HCC tissues and cell lines, and its downregulation was closely correlated with aggressive clinicopathological features and poor prognosis of HCC patients. Overexpression of miR-592 inhibited aerobic glycolysis and proliferation in HCC cells in vitro. Conversely, knockdown of miR-592 promoted HCC growth in both subcutaneous injection and orthotopic liver tumor implantation models in vivo. Mechanistically, miR-592 downregulation in human HCCs was correlated with an upregulation of WD repeat and SOCS box containing 1 (WSB1). We further showed that miR-592 directly binds to the 3'-UTR of the WSB1 gene, thus disrupting hypoxia inducible factor-1α (HIF-1α) protein stabilization. In turn, overexpression of WSB1 in HCC cells rescued decreased HIF-1α expression, glucose uptake, and HCC growth induced by miR-592. Collectively, our clinical data and functional studies suggest that miR-592 is a new robust inhibitor of the Warburg effect and a promising therapeutic target for HCC treatment.

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“…Dysregulation of wsb1 expression has been documented in diverse cancer cell types, including neuroblastoma (NB), hepatocellular carcinoma (HCC), pancreatic, osteosarcoma and breast cancer cells [ 1 , 6 , 8 , 23 , 29 , 36 , 37 , 39 ]. Copy number changes of wsb1 can be identified in cases of neuroblastoma.…”

Section: Wsb1 and Cancermentioning

confidence: 99%

“…As reported in Ensembl, the gene encodes for 9 exons, and alternative splicing results in 17 putative transcripts ( http://uswest.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000109046;r=17:27294076-27315926 ). However, only three major alternative wsb1 transcripts have been reported in the literature [ 1 , 3 , 36 ]. It was shown, through Northern blotting of different human tissues, that the three wsb1 mRNA were highly expressed in the brain, heart, kidney, and placenta [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

WSB1: from homeostasis to hypoxia

et al. 2016

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The wsb1 gene has been identified to be important in developmental biology and cancer. A complex transcriptional regulation of wsb1 yields at least three functional transcripts. The major expressed isoform, WSB1 protein, is a substrate recognition protein within an E3 ubiquitin ligase, with the capability to bind diverse targets and mediate ubiquitinylation and proteolytic degradation. Recent data suggests a new role for WSB1 as a component of a neuroprotective pathway which results in modification and aggregation of neurotoxic proteins such as LRRK2 in Parkinson’s Disease, via an unusual mode of protein ubiquitinylation.WSB1 is also involved in thyroid hormone homeostasis, immune regulation and cellular metabolism, particularly glucose metabolism and hypoxia. In hypoxia, wsb1 is a HIF-1 target, and is a regulator of the degradation of diverse proteins associated with the cellular response to hypoxia, including HIPK2, RhoGDI2 and VHL. Major roles are to both protect HIF-1 function through degradation of VHL, and decrease apoptosis through degradation of HIPK2. These activities suggest a role for wsb1 in cancer cell proliferation and metastasis. As well, recent work has identified a role for WSB1 in glucose metabolism, and perhaps in mediating the Warburg effect in cancer cells by maintaining the function of HIF1. Furthermore, studies of cancer specimens have identified dysregulation of wsb1 associated with several types of cancer, suggesting a biologically relevant role in cancer development and/or progression.Recent development of an inducible expression system for wsb1 could aid in the further understanding of the varied functions of this protein in the cell, and roles as a potential oncogene and neuroprotective protein.

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Potential role of WSB1 isoforms in growth and survival of neuroblastoma cells

Abstract: Our results point to a possible differential role of WSB1 isoforms in NB and suggest WSB1(3) as a target for therapy in NB.

Cited by 10 publications

References 17 publications

Hypoxia-Induced WSB1 Promotes the Metastatic Potential of Osteosarcoma Cells

Hypoxia-Induced WSB1 Promotes the Metastatic Potential of Osteosarcoma Cells

miR-592/WSB1/HIF-1α axis inhibits glycolytic metabolism to decrease hepatocellular carcinoma growth

WSB1: from homeostasis to hypoxia

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