The Transcription Factor ZNF395 Is Required for the Maximal Hypoxic Induction of Proinflammatory Cytokines in U87‐MG Cells

Herwartz, Christine; Castillo-Juárez, Paola; Schröder, Linda; Barrón, Blanca Lilia; Steger, Gertrud

doi:10.1155/2015/804264

Cited by 14 publications

(19 citation statements)

References 49 publications

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“…U87-MG cells have been shown to express LIF, 24 and we have also proved in this work that LIF is released to the incubation medium, at concentrations within the dynamic range of the AlphaScreen assay that we have developed. The assay was pharmacologically validated.…”

supporting

confidence: 58%

“…A number of factors have also been found to induce LIF in nonneural tissues, including TNF-α, transforming growth factor beta (TGF-β), granulocyte-colony stimulating factor (G-CSF), interleukin 1 beta (IL-1β), and immunoglobulin-like factor (IGF). Some of these factors are also expressed in U87 cells, 24 so the induction of a paracrine or autocrine mechanism of regulation by the identified compounds could be hypothesized. In Muller glial cells, activation of the TLR2/ NF-kappa B is necessary for induction of LIF expression, and LIF can autoregulate its own expression after that induction.…”

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confidence: 99%

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Discovery of Enhancers of the Secretion of Leukemia Inhibitory Factor for the Treatment of Multiple Sclerosis

et al. 2016

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These authors contributed equally to this work.Received Oct 30, 2015, and AbstractMultiple sclerosis (MS) is an autoimmune neurodegenerative disease that involves activation of T cells, microglia, and astrocytes. There is a clear unmet medical need for MS, as current therapies reduce the relapse rate, but are unable to prevent the neurological deterioration. Leukemia inhibitory factor (LIF) is a proinflammatory cytokine that can also positively modulate the immune response, by inducing the inhibition of myelin-reactive T H 17 differentiation, and by promoting oligodendrocyte-mediated myelination. The aim of this project was to find central nervous system (CNS)-permeable and orally available small molecules that upregulate production of endogenous LIF. We describe here the development of a phenotypic assay and screening of 1.7 million compounds to identify LIF enhancers using U87 MG cells. Five chemically tractable series of compounds and a few singletons were selected for further progression. Some of them were also active in a different LIF-expressing cell line and in primary rat astrocytes. Although further studies would be required to deconvolute the targets involved in LIF induction and to confirm activity of hits in more disease-relevant assays, our results have demonstrated the potential of the phenotypic approach to identify specific and chemically tractable small molecules that trigger the production of LIF in relevant cell lines.

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confidence: 58%

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confidence: 99%

Discovery of Enhancers of the Secretion of Leukemia Inhibitory Factor for the Treatment of Multiple Sclerosis

et al. 2016

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“…ZNF395 , which encodes a protein having one C2H2-type zinc finger domain, is overexpressed in various tumors including kidney cancer [22] and has been reported to be induced by hypoxia involved in IKK signaling [23]. The ZNF395 gene is located at 8p21, and TENET identified hypomethylation of enhancer probe cg12116192 (located ~500 kb from the TSS of ZNF395 ) to be positively associated with the expression of the ZNF395 gene (Fig.…”

Section: Resultsmentioning

confidence: 99%

Identification of activated enhancers and linked transcription factors in breast, prostate, and kidney tumors by tracing enhancer networks using epigenetic traits

Rhie

Guo

Tak

et al. 2016

Epigenetics & Chromatin

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BackgroundAlthough technological advances now allow increased tumor profiling, a detailed understanding of the mechanisms leading to the development of different cancers remains elusive. Our approach toward understanding the molecular events that lead to cancer is to characterize changes in transcriptional regulatory networks between normal and tumor tissue. Because enhancer activity is thought to be critical in regulating cell fate decisions, we have focused our studies on distal regulatory elements and transcription factors that bind to these elements.ResultsUsing DNA methylation data, we identified more than 25,000 enhancers that are differentially activated in breast, prostate, and kidney tumor tissues, as compared to normal tissues. We then developed an analytical approach called Tracing Enhancer Networks using Epigenetic Traits that correlates DNA methylation levels at enhancers with gene expression to identify more than 800,000 genome-wide links from enhancers to genes and from genes to enhancers. We found more than 1200 transcription factors to be involved in these tumor-specific enhancer networks. We further characterized several transcription factors linked to a large number of enhancers in each tumor type, including GATA3 in non-basal breast tumors, HOXC6 and DLX1 in prostate tumors, and ZNF395 in kidney tumors. We showed that HOXC6 and DLX1 are associated with different clusters of prostate tumor-specific enhancers and confer distinct transcriptomic changes upon knockdown in C42B prostate cancer cells. We also discovered de novo motifs enriched in enhancers linked to ZNF395 in kidney tumors.ConclusionsOur studies characterized tumor-specific enhancers and revealed key transcription factors involved in enhancer networks for specific tumor types and subgroups. Our findings, which include a large set of identified enhancers and transcription factors linked to those enhancers in breast, prostate, and kidney cancers, will facilitate understanding of enhancer networks and mechanisms leading to the development of these cancers.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-016-0102-4) contains supplementary material, which is available to authorized users.

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“…ZNF395 has been shown to bind to the promoters of Huntington gene (101) and interferon-induced genes, and to cause upregulation of cancer-related genes (MACC1, PEG10, CALCOCO1, and MEF2C; ref. 104) and proangiogenic chemokines including IL6 and IL8 under hypoxia (105). It remains to be elucidated in future studies the precise mechanism contributing to ZNF395's tumorigenic role.…”

Section: Discussionmentioning

confidence: 96%

“…MCF7 cells under hypoxia (but not normoxia) share similar H3K27ac profiles as 786-O (29). Although ZNF395 is highly expressed in ccRCC, its low basal expression can be upregulated upon hypoxia in other cancer types, including glioblastoma and skin cancer (104,105). Targeting ZNF395 or its downstream effectors in future studies may be therapeutically relevant to both ccRCC and other hypoxic solid malignancies.…”

Section: Discussionmentioning

confidence: 98%

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

et al. 2017

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Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel-Lindau ( VHL ) tumor suppressor. Roles for noncoding cis -regulatory aberrations in ccRCC tumorigenesis, however, remain unclear. Analyzing 10 primary tumor/normal pairs and 9 cell lines across 79 chromatin profi les, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specifi c aspects of malignancy. Superenhancer profi ling identifi ed ZNF395 as a ccRCCspecifi c and VHL-regulated master regulator whose depletion causes near-complete tumor elimination in vitro and in vivo . VHL loss predominantly drives enhancer/superenhancer deregulation more so than promoters, with acquisition of active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes. Mechanistically, VHL loss stabilizes HIF2α-HIF1β heterodimer binding at enhancers, subsequently recruiting histone acetyltransferase p300 without overtly affecting preexisting promoter-enhancer interactions. Subtype-specifi c driver mutations such as VHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression. SIGnIFICAnCE:Comprehensive epigenomic profi ling of ccRCC establishes a compendium of somatically altered cis -regulatory elements, uncovering new potential targets including ZNF395, a ccRCC master regulator. Loss of VHL , a ccRCC signature event, causes pervasive enhancer malfunction, with binding of enhancer-centric HIF2α and recruitment of histone acetyltransferase p300 at preexisting lineage-specifi c promoter-enhancer complexes. Cancer Discov; 7(11); 1284-305.

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The Transcription Factor ZNF395 Is Required for the Maximal Hypoxic Induction of Proinflammatory Cytokines in U87‐MG Cells

Cited by 14 publications

References 49 publications

Discovery of Enhancers of the Secretion of Leukemia Inhibitory Factor for the Treatment of Multiple Sclerosis

Discovery of Enhancers of the Secretion of Leukemia Inhibitory Factor for the Treatment of Multiple Sclerosis

Identification of activated enhancers and linked transcription factors in breast, prostate, and kidney tumors by tracing enhancer networks using epigenetic traits

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

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