Siah2 control of T-regulatory cells limits anti-tumor immunity

Scortegagna, Marzia; Hockemeyer, Kathryn; Dolgalev, Igor; Poźniak, Joanna; Rambow, Florian; Yan, Li; Feng, Yongmei; Tinoco, Roberto; Otero, Dennis C.; Zhang, Tongwu; Brown, Kevin M.; Bosenberg, Marcus W.; Bradley, Linda M.; Marine, Jean–Christophe; Aifantis, Ioannis; Ronai, Ze’ev A.

doi:10.1038/s41467-019-13826-7

Cited by 17 publications

(15 citation statements)

References 68 publications

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“…Very recently, Scortegagna et al identified the role of the E3 ubiquitin ligase SIAH2 (Seven in absentia homolog 2) in the regulation of T-regulatory (Treg) cells [ 118 ]. In Siah2 −/− nude mice inoculated with melanoma cells, tumor-infiltrating Treg cells were dramatically less proliferative, leading to the inhibition of tumor growth, compared to Treg from wild-type mice.…”

Section: Ubiquitination and Resistancementioning

confidence: 99%

“…In Siah2 −/− nude mice inoculated with melanoma cells, tumor-infiltrating Treg cells were dramatically less proliferative, leading to the inhibition of tumor growth, compared to Treg from wild-type mice. Moreover, the tumor growth was drastically reduced when Siah2 −/− mice were challenged with anti-PD-1 treatment [ 118 ]. The authors concluded that SIAH2 controls Treg-cell recruitment and its loss in the host sensitizes melanoma to anti-PD-1 treatment.…”

Section: Ubiquitination and Resistancementioning

confidence: 99%

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An Update on the Role of Ubiquitination in Melanoma Development and Therapies

Soysouvanh

Giuliano

Habel

et al. 2021

JCM

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The ubiquitination system plays a critical role in regulation of large array of biological processes and its alteration has been involved in the pathogenesis of cancers, among them cutaneous melanoma, which is responsible for the most deaths from skin cancers. Over the last decades, targeted therapies and immunotherapies became the standard therapeutic strategies for advanced melanomas. However, despite these breakthroughs, the prognosis of metastatic melanoma patients remains unoptimistic, mainly due to intrinsic or acquired resistances. Many avenues of research have been investigated to find new therapeutic targets for improving patient outcomes. Because of the pleiotropic functions of ubiquitination, and because each step of ubiquitination is amenable to pharmacological targeting, much attention has been paid to the role of this process in melanoma development and resistance to therapies. In this review, we summarize the latest data on ubiquitination and discuss the possible impacts on melanoma treatments.

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Section: Ubiquitination and Resistancementioning

confidence: 99%

Section: Ubiquitination and Resistancementioning

confidence: 99%

An Update on the Role of Ubiquitination in Melanoma Development and Therapies

Soysouvanh

Giuliano

Habel

et al. 2021

JCM

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“…Wang et al (2019) revealed that ZMYND10 plays an inhibitory role within the miR145-5p/NEDD9 signaling pathway, this ultimately leads to suppression of BRCA tumorigenesis. SIAH2, an E3 ubiquitin ligase, has key functions in multiple fundamental cellular processes: hypoxia, intracellular signaling, and the unfolded protein response to name a few (Scortegagna et al, 2020;Ma et al, 2019). SIAH2 protein expression was shown to be able to predict ER status and tamoxifen therapy outcome due to its inverse relationship within a metastatic BRCA cohort (van der Willik et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of a novel zinc finger protein-related gene-based prognostic model for breast cancer

Liu

et al. 2021

PeerJ

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Background Breast invasive carcinoma (BRCA) is a commonly occurring malignant tumor. Zinc finger proteins (ZNFs) constitute the largest transcription factor family in the human genome and play a mechanistic role in many cancers’ development. The prognostic value of ZNFs has yet to be approached systematically for BRCA. Methods We analyzed the data of a training set from The Cancer Genome Atlas (TCGA) database and two validation cohort from GSE20685 and METABRIC datasets, composed of 3,231 BRCA patients. After screening the differentially expressed ZNFs, univariate Cox regression, LASSO, and multiple Cox regression analysis were performed to construct a risk-based predictive model. ESTIMATE algorithm, single-sample gene set enrichment analysis (ssGSEA), and gene set enrichment analyses (GSEA) were utilized to assess the potential relations among the tumor immune microenvironment and ZNFs in BRCA. Results In this study, we profiled ZNF expression in TCGA based BRCA cohort and developed a novel prognostic model based on 14 genes with ZNF relations. This model was composed of high and low-score groups for BRCA classification. Based upon Kaplan-Meier survival curves, risk-status-based prognosis illustrated significant differences. We integrated the 14 ZNF-gene signature with patient clinicopathological data for nomogram construction with accurate 1-, 3-, and 5-overall survival predictive capabilities. We then accessed the Genomics of Drug Sensitivity in Cancer database for therapeutic drug response prediction of signature-defined BRCA patient groupings for our selected TCGA population. The signature also predicts sensitivity to chemotherapeutic and molecular-targeted agents in high- and low-risk patients afflicted with BRCA. Functional analysis suggested JAK STAT, VEGF, MAPK, NOTCH TOLL-like receptor, NOD-like receptor signaling pathways, apoptosis, and cancer-based pathways could be key for ZNF-related BRCA development. Interestingly, based on the results of ESTIMATE, ssGSEA, and GSEA analysis, we elucidated that our ZNF-gene signature had pivotal regulatory effects on the tumor immune microenvironment for BRCA. Conclusion Our findings shed light on the potential contribution of ZNFs to the pathogenesis of BRCA and may inform clinical practice to guide individualized treatment.

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“…A recent study has linked SIAH2 to the cellular response to oxidative stress, remodeling of the tumor microenvironment, and tumor progression by targeting NRF1 for degradation in breast cancer ( Ma et al, 2019 ). Another recent study has implicated SIAH2 in immune evasion of melanoma by promoting Treg proliferation via degradation of p27 ( Scortegagna et al, 2020 ).…”

Section: Regulation Of the Siah2-hif-1 Axis By Protein Kinases And Camentioning

confidence: 99%

Regulation of the SIAH2-HIF-1 Axis by Protein Kinases and Its Implication in Cancer Therapy

2021

Front. Cell Dev. Biol.

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The cellular response to hypoxia is a key biological process that facilitates adaptation of cells to oxygen deprivation (hypoxia). This process is critical for cancer cells to adapt to the hypoxic tumor microenvironment resulting from rapid tumor growth. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor and a master regulator of the cellular response to hypoxia. The activity of HIF-1 is dictated primarily by its alpha subunit (HIF-1α), whose level and/or activity are largely regulated by an oxygen-dependent and ubiquitin/proteasome-mediated process. Prolyl hydroxylases (PHDs) and the E3 ubiquitin ligase Von Hippel-Lindau factor (VHL) catalyze hydroxylation and subsequent ubiquitin-dependent degradation of HIF-1α by the proteasome. Seven in Absentia Homolog 2 (SIAH2), a RING finger-containing E3 ubiquitin ligase, stabilizes HIF-1α by targeting PHDs for ubiquitin-mediated degradation by the proteasome. This SIAH2-HIF-1 signaling axis is important for maintaining the level of HIF-1α under both normoxic and hypoxic conditions. A number of protein kinases have been shown to phosphorylate SIAH2, thereby regulating its stability, activity, or substrate binding. In this review, we will discuss the regulation of the SIAH2-HIF-1 axis via phosphorylation of SIAH2 by these kinases and the potential implication of this regulation in cancer biology and cancer therapy.

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Siah2 control of T-regulatory cells limits anti-tumor immunity

Cited by 17 publications

References 68 publications

An Update on the Role of Ubiquitination in Melanoma Development and Therapies

An Update on the Role of Ubiquitination in Melanoma Development and Therapies

Identification and validation of a novel zinc finger protein-related gene-based prognostic model for breast cancer

Regulation of the SIAH2-HIF-1 Axis by Protein Kinases and Its Implication in Cancer Therapy

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