Estrogen receptor coactivator Mediator Subunit 1 (MED1) as a tissue-specific therapeutic target in breast cancer

Leonard, Marissa; Zhang, Xiaoting

doi:10.1631/jzus.b1900163

Cited by 22 publications

(17 citation statements)

References 57 publications

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“…To date, many studies have demonstrated the role of MED1 in the development of cancer [ 23 , 24 ], but there are few studies on the effect of MED1 in cardiovascular disease. Although there are reports on the fatal effect of MED1 deletion in cardiomyocytes [ 25 ] and the protective effect of MED1 deletion in macrophages on atherosclerosis [ 26 ], the role of MED1 in cardiovascular disease remains unknown.…”

Section: Introductionmentioning

confidence: 99%

MED1 Deficiency in Macrophages Accelerates Intimal Hyperplasia via ROS Generation and Inflammation

Zhang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Mediator complex subunit 1 (MED1) is a component of the mediator complex and functions as a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Previously, we showed that MED1 in macrophages has a protective effect on atherosclerosis; however, the effect of MED1 on intimal hyperplasia and mechanisms regulating proinflammatory cytokine production after macrophage MED1 deletion are still unknown. In this study, we report that MED1 macrophage-specific knockout (MED1ΔMac) mice showed aggravated neointimal hyperplasia, vascular smooth muscle cells (VSMCs), and macrophage accumulation in injured arteries. Moreover, MED1ΔMac mice showed increased proinflammatory cytokine production after an injury to the artery. After lipopolysaccharide (LPS) treatment, MED1ΔMac macrophages showed increased generation of reactive oxygen species (ROS) and reduced expression of peroxisome proliferative activated receptor gamma coactivator-1α (PGC1α) and antioxidant enzymes, including catalase and glutathione reductase. The overexpression of PGC1α attenuated the effects of MED1 deficiency in macrophages. In vitro, conditioned media from MED1ΔMac macrophages induced more proliferation and migration of VSMCs. To explore the potential mechanisms by which MED1 affects inflammation, macrophages were treated with BAY11-7082 before LPS treatment, and the results showed that MED1ΔMac macrophages exhibited increased expression of phosphorylated-p65 and phosphorylated signal transducer and activator of transcription 1 (p-STAT1) compared with the control macrophages, suggesting the enhanced activation of NF-κB and STAT1. In summary, these data showed that MED1 deficiency enhanced inflammation and the proliferation and migration of VSMCs in injured vascular tissue, which may result from the activation of NF-κB and STAT1 due to the accumulation of ROS.

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Section: Introductionmentioning

confidence: 99%

MED1 Deficiency in Macrophages Accelerates Intimal Hyperplasia via ROS Generation and Inflammation

Zhang

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…It also interacts with genes regulating GAG initiation. This gene is known to promote colon cancer metastasis through ATF2 interactions 45 Mediator subunit 1 (MED1) is a transcriptional cofactor known to comprise enhancer complexes, and is regulated by hormone signals in breast, prostate, and bladder cancers 46,47 .…”

Section: Critical Role For Runx3 In Terminal Fucosylationmentioning

confidence: 99%

“…For example, it mediates the binding between the estrogen receptor and a mediator complex responsible for recruiting RNA polymerase II in breast cancer complexes 47 . This TF was enriched to complex N-linked glycan synthesis pathways through the regulation of GANAB.…”

Section: Critical Role For Runx3 In Terminal Fucosylationmentioning

confidence: 99%

A systems based framework to computationally predict putative transcription factors and signaling pathways regulating glycan biosynthesis

Groth¹,

Neelamegham

2020

Preprint

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Glycosylation is a common, complex, non-linear post-translational modification. The biosynthesis of these structures is regulated by a set of 'glycogenes'. The role of transcription factors (TFs) in regulating the glycogenes and related glycosylation pathways is yet unknown. This manuscript presents a multi-OMICs data-mining framework to computationally predict tissue specific TF activities and cell signaling pathways regulating the biosynthesis of specific glycan structures. It combines existing ChIP-Seq (Chromatin ImmunoPrecipitation Sequencing) and RNA-Seq data to reveal 20,617 potentially significant TF-glycogene relationships. This includes interactions involving 524 unique TFs and 341 glycogenes that span 29 TCGA (The Cancer Genome Atlas) cancer types. Here, TF-glycogene interactions appeared in clusters or 'communities', suggesting that they may collectively drive changes in sets of carbohydrate structures rather than unique glycans as disease progresses. Upon applying the Fisher's exact test along with glycogene pathway ontology, we identify TFs that may specifically regulate the biosynthesis of individual glycan types. Integration with knowledge from the Reactome database established the link between cell signaling pathways, transcription factors, glycogene expression, and glycosylation pathways. Whereas analysis results are presented for all 29 cancer types, specific focus is placed on human luminal and basal breast cancer disease progression. This implicates a key role for TGF-β and Wnt signaling in regulating TFs that control both tumorigenesis and cellular glycosylation. Overall, the computational predictions in this manuscript present a rich dataset that is ripe for experimental testing and hypotheses validation.

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“…Besides the pioneer factor to recruit ER to chromatin, Mediator Subunit 1 (MED1) brings a mediator complex to the ER via direct association with the ER, thereby playing an important role in ER-derived target gene expression [126,127]. Consistent with HER2 promoting the endocrine resistance of ER + ve BCs, MED1 expression was correlated with HER2 expression and facilitated the communication between ER and HER2, which contributed to HER2-derived promotion of endocrine resistance; downregulation of MED1 reduced the resistance [128,129,130].…”

Section: Mechanisms Underlying Bcsc Enrichment Following the Develmentioning

confidence: 99%

The Central Contributions of Breast Cancer Stem Cells in Developing Resistance to Endocrine Therapy in Estrogen Receptor (ER)-Positive Breast Cancer

Rodriguez

Ramkairsingh

Lin

et al. 2019

Cancers

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Breast cancer stem cells (BCSC) play critical roles in the acquisition of resistance to endocrine therapy in estrogen receptor (ER)-positive (ER + ve) breast cancer (BC). The resistance results from complex alterations involving ER, growth factor receptors, NOTCH, Wnt/β-catenin, hedgehog, YAP/TAZ, and the tumor microenvironment. These mechanisms are likely converged on regulating BCSCs, which then drive the development of endocrine therapy resistance. In this regard, hormone therapies enrich BCSCs in ER + ve BCs under both pre-clinical and clinical settings along with upregulation of the core components of “stemness” transcriptional factors including SOX2, NANOG, and OCT4. SOX2 initiates a set of reactions involving SOX9, Wnt, FXY3D, and Src tyrosine kinase; these reactions stimulate BCSCs and contribute to endocrine resistance. The central contributions of BCSCs to endocrine resistance regulated by complex mechanisms offer a unified strategy to counter the resistance. ER + ve BCs constitute approximately 75% of BCs to which hormone therapy is the major therapeutic approach. Likewise, resistance to endocrine therapy remains the major challenge in the management of patients with ER + ve BC. In this review we will discuss evidence supporting a central role of BCSCs in developing endocrine resistance and outline the strategy of targeting BCSCs to reduce hormone therapy resistance.

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Estrogen receptor coactivator Mediator Subunit 1 (MED1) as a tissue-specific therapeutic target in breast cancer

Cited by 22 publications

References 57 publications

MED1 Deficiency in Macrophages Accelerates Intimal Hyperplasia via ROS Generation and Inflammation

MED1 Deficiency in Macrophages Accelerates Intimal Hyperplasia via ROS Generation and Inflammation

A systems based framework to computationally predict putative transcription factors and signaling pathways regulating glycan biosynthesis

The Central Contributions of Breast Cancer Stem Cells in Developing Resistance to Endocrine Therapy in Estrogen Receptor (ER)-Positive Breast Cancer

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