<scp>Genome‐wide</scp> estrogen receptor β chromatin binding in human colon cancer cells reveals its tumor suppressor activity

Indukuri, Rajitha; Jafferali, Mohammed Hakim; Song, Dandan; Damdimopoulos, Anastasios; Hases, Linnea; Zhao, Chunyan; Archer, Amena; Williams, Cecilia

doi:10.1002/ijc.33573

Cited by 13 publications

(23 citation statements)

References 71 publications

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“…Furthermore, ERB-041-treated cell lines demonstrated significantly decreased migration and survival, and enhanced apoptotic activity as witnessed by increased caspase-3 and apoptotic blebs [ 35 ]. Recently, Indukuri et al [ 36 ] showed that in several cell lines (HT29, SW480) ERβ may bind chromatin, regulating several cystatin genes, and in close proximity of the gene promoter, in both cell lines. Cystatin 5 is indeed a proposed tumor suppressor in CRC.…”

Section: Studies In Cell Linesmentioning

confidence: 99%

Estrogen Receptors in Colorectal Cancer: Facts, Novelties and Perspectives

et al. 2021

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Colorectal cancer (CRC) is the second cause of cancer-related death in both sexes worldwide. As pre-menopausal women are less likely to develop CRC compared to age-matched men, a protective role for estrogens has been hypothesized. Indeed, two isoforms of nuclear estrogen receptors (ER) have been described: ERα and ERβ. While the binding of 17beta-estradiol to ERα activates anti-apoptotic pathways, the interaction with ERβ activates caspase-3, inducing apoptosis. In this regard, several pieces of evidence show that ERβ tends to be under-regulated in advanced adenomas and CRC, with an opposite trend for ERα. Furthermore, ERβ stimulation slows adenomatous polyp growth and modulates relevant CRC pathways. Based on such considerations, dietary modulation of ER is promising, particularly in subjects with genetic predisposition for CRC. Nevertheless, the main limitation is the lack of clinical trials on a large population scale.

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Section: Studies In Cell Linesmentioning

confidence: 99%

Estrogen Receptors in Colorectal Cancer: Facts, Novelties and Perspectives

et al. 2021

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“…For example, a crosstalk between ESR with NF-κB proteins is well-established and has been suggested to explain the immunosuppressive and anti-inflammatory effects of estrogens [40,41]. Similarly, crosstalk between ESR1 and ESR2 and the AP-1 (FOS/JUN) complex is recognized [18,42,43] as well as with the RUNX transcription factors [44]. A crosstalk between ESR and NR4A2 is less well-established.…”

Section: Discussionmentioning

confidence: 99%

“…In order to validate if the ESR2 binding of the genes identified in the ChIP-seq increased in response to DPN treatment, Granta-519-ESR2 cells were treated with 100 nM DPN or vehicle for 2 h, after which a selected number of genes, FOS, FOSB, VEGFA, CXCR4, MALAT1, and NEAT1, were analyzed by ChIP-qPCR. GREB1 was used as a positive control since it was previously shown by ChIP to bind ESR2 when analyzed using the PPZ0506 antibody [18]. When comparing DPN-to vehicle-treated Granta-519-ESR2 cells, the enrichment of ESR2 binding to CXCR4, GREB1, VEGFA, NEAT1, and FOS was detected following the DPN treatment, demonstrating that the binding of ESR2 to these genes was increased upon ligand binding.…”

Section: Esr2 Binding To the Regulated Genes Is Enhanced Following Dp...mentioning

confidence: 99%

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Estrogen Receptor β (ESR2) Transcriptome and Chromatin Binding in a Mantle Cell Lymphoma Tumor Model Reveal the Tumor-Suppressing Mechanisms of Estrogens

Huang

Indukuri

et al. 2022

Cancers

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Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma with one of the highest male-to-female incidence ratios. The reason for this is not clear, but epidemiological as well as experimental data have suggested a role for estrogens, particularly acting through estrogen receptor β (ESR2). To study the ESR2 effects on MCL progression, MCL cells sensitive and resistant to the Bruton tyrosine kinase inhibitor ibrutinib were grafted to mice and treated with the ESR2-selective agonist diarylpropionitrile (DPN). The results showed that the DPN treatment of mice grafted with both ibrutinib-sensitive and -resistant MCL tumors resulted in impaired tumor progression. To identify the signaling pathways involved in the impaired tumor progression following ESR2 agonist treatment, the transcriptome and ESR2 binding to target genes were investigated by genome-wide chromatin immunoprecipitation in Granta-519 MCL tumors. DPN-regulated genes were enriched in several biological processes that included cell–cell adhesion, endothelial–mesenchymal transition, nuclear factor-kappaB signaling, vasculogenesis, lymphocyte proliferation, and apoptosis. In addition, downregulation of individual genes, such as SOX11 and MALAT1, that play a role in MCL progression was also observed. Furthermore, the data suggested an interplay between the lymphoma cells and the tumor microenvironment in response to the ESR2 agonist. In conclusion, the results clarify the mechanisms by which estrogens, via ESR2, impair MCL tumor progression and provide a possible explanation for the sex-dependent difference in incidence. Furthermore, targeting ESR2 with a selective agonist may be an additional option when considering the treatment of both ibrutinib-sensitive and -resistant MCL tumors.

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“…Importantly, estradiol downregulated genes that are known to induce cell migration and upregulated those mediating inhibitory actions on migratory activity. In this context, estradiol down regulated: ZFYVE16, a FYVE zink finger family protein (also called endofin) that regulates cell adhesion and induces cell migration [ 46 ] by regulating TGFβ signaling pathway and is downregulated by ER-β in cancer cells [ 47 ]; and epiregulin, which stimulates cell migration via MAPK activation [ 57 ]. Additionally, estradiol downregulated multiple other genes known to induce cell migration, i.e., B3GNT5, a sphingolipid metabolic enzyme [ 58 ]; FADS1 [ 44 ], MIR1908 (a cholesterol responsive miRNA [ 45 ]); nucleoporin 58 kDa (NUP58) [ 55 ]; TOPORS [ 53 , 54 ]; Six homeobox 4 [ 48 ]; Retinoblastoma binding protein-9 (RBBP9) [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Estradiol Inhibits Human Brain Vascular Pericyte Migration Activity: A Functional and Transcriptomic Analysis

Kurmann

Okoniewski

Dubey

2021

Cells

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Stroke is the third leading cause of mortality in women and it kills twice as many women as breast cancer. A key role in the pathophysiology of stroke plays the disruption of the blood–brain barrier (BBB) within the neurovascular unit. While estrogen induces vascular protective actions, its influence on stroke remains unclear. Moreover, experiments assessing its impact on endothelial cells to induce barrier integrity are non-conclusive. Since pericytes play an active role in regulating BBB integrity and function, we hypothesize that estradiol may influence BBB by regulating their activity. In this study using human brain vascular pericytes (HBVPs) we investigated the impact of estradiol on key pericyte functions known to influence BBB integrity. HBVPs expressed estrogen receptors (ER-α, ER-β and GPER) and treatment with estradiol (10 nM) inhibited basal cell migration but not proliferation. Since pericyte migration is a hallmark for BBB disruption following injury, infection and inflammation, we investigated the effects of estradiol on TNFα-induced PC migration. Importantly, estradiol prevented TNFα-induced pericyte migration and this effect was mimicked by PPT (ER-α agonist) and DPN (ER-β agonist), but not by G1 (GPR30 agonist). The modulatory effects of estradiol were abrogated by MPP and PHTPP, selective ER-α and ER-β antagonists, respectively, confirming the role of ER-α and ER-β in mediating the anti-migratory actions of estrogen. To delineate the intracellular mechanisms mediating the inhibitory actions of estradiol on PC migration, we investigated the role of AKT and MAPK activation. While estradiol consistently reduced the TNFα-induced MAPK and Akt phosphorylation, only the inhibition of MAPK, but not Akt, significantly abrogated the migratory actions of TNFα. In transendothelial electrical resistance measurements, estradiol induced barrier function (TEER) in human brain microvascular endothelial cells co-cultured with pericytes, but not in HBMECs cultured alone. Importantly, transcriptomics analysis of genes modulated by estradiol in pericytes showed downregulation of genes known to increase cell migration and upregulation of genes known to inhibit cell migration. Taken together, our findings provide the first evidence that estradiol modulates pericyte activity and thereby improves endothelial integrity.

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Genome‐wide estrogen receptor β chromatin binding in human colon cancer cells reveals its tumor suppressor activity

Cited by 13 publications

References 71 publications

Estrogen Receptors in Colorectal Cancer: Facts, Novelties and Perspectives

Estrogen Receptors in Colorectal Cancer: Facts, Novelties and Perspectives

Estrogen Receptor β (ESR2) Transcriptome and Chromatin Binding in a Mantle Cell Lymphoma Tumor Model Reveal the Tumor-Suppressing Mechanisms of Estrogens

Estradiol Inhibits Human Brain Vascular Pericyte Migration Activity: A Functional and Transcriptomic Analysis

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