Activation of peroxisome proliferator-activated receptor gamma in mammary epithelial cells upregulates the expression of tumor suppressor Cyld to mediate growth inhibition and anti-inflammatory effects

Pseftogas, Athanasios; Gonidas, Christos; Mosialos, George

doi:10.1016/j.biocel.2016.11.011

Cited by 9 publications

(8 citation statements)

References 29 publications

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“…Multiple lines of evidence from cell line models and human patient samples have implicated CYLD in breast cancer suppression [28][29][30][31][32][33][34][35]. Downregulation of CYLD expression can augment the viability, migratory capacity, and anchorage-independent growth of basal and luminal human breast cancer cell lines [28][29][30][31][33][34][35]. In addition, CYLD protein downregulation was correlated with poor prognosis in primary breast cancer patients [35].…”

Section: Introductionmentioning

confidence: 99%

The Tumor Suppressor CYLD Inhibits Mammary Epithelial to Mesenchymal Transition by the Coordinated Inhibition of YAP/TAZ and TGFβ Signaling

Pseftogas

Xanthopoulos

Poutahidis

et al. 2020

Cancers

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Downregulation of the cylindromatosis (CYLD) tumor suppressor has been associated with breast cancer development and progression. Here, we report a critical role for CYLD in maintaining the phenotype of mammary epithelial cells in vitro and in vivo. CYLD downregulation or inactivation induced an epithelial to mesenchymal transition of mammary epithelial cells that was dependent on the concomitant activation of the transcription factors Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) and transforming growth factor beta (TGFβ)signaling. CYLD inactivation enhanced the nuclear localization of YAP/TAZ and the phosphorylation of Small Mothers Against Decapentaplegic (SMAD)2/3 proteins in confluent cell culture conditions. Consistent with these findings were the hyperplastic alterations of CYLD-deficient mouse mammary epithelia, which were associated with enhanced nuclear expression of the YAP/TAZ transcription factors. Furthermore, in human breast cancer samples, downregulation of CYLD expression correlates with enhanced YAP/TAZ-regulated target gene expression. Our results identify CYLD as a critical regulator of a signaling node that prevents the coordinated activation of YAP/TAZ and the TGFβ pathway in mammary epithelial cells, in order to maintain their phenotypic identity and homeostasis. Consequently, they provide a novel conceptual framework that supports and explains a causal implication of deficient CYLD expression in aggressive human breast cancers.

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Section: Introductionmentioning

confidence: 99%

The Tumor Suppressor CYLD Inhibits Mammary Epithelial to Mesenchymal Transition by the Coordinated Inhibition of YAP/TAZ and TGFβ Signaling

Pseftogas

Xanthopoulos

Poutahidis

et al. 2020

Cancers

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“…It may also be possible that the rare variant contributes to the severe phenotype, for fatty acid-binding proteins (FABP) are crucial in the control of intracellular signaling pathways of peroxisome proliferatoractivated receptor-c (PPAR-c) and NF-jB receptors, 9 while PPAR-c is a regulator of CYLD transcription in mammary epithelial cells. 10 In conclusion, we identified the pathogenic mutation responsible for hypotrichosis and the FABP12 variant which may just be coincidental in the accompanying MFT in individuals with no CYLD mutations in this family. So far as we know, MUHH accompanied by MFT has not been reported before.…”

Section: Discussionmentioning

confidence: 62%

“…Third, it is still uncertain whether other carriers of the corresponding variant (rs536105592) are the patients with MFT. It may also be possible that the rare variant contributes to the severe phenotype, for fatty acid‐binding proteins (FABP) are crucial in the control of intracellular signaling pathways of peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) and NF‐κB receptors, while PPAR‐γ is a regulator of CYLD transcription in mammary epithelial cells …”

Section: Discussionmentioning

confidence: 99%

Marie Unna hereditary hypotrichosis accompanied by multiple familial trichoepithelioma in a Chinese family

Huang

Cai

Ren

et al. 2019

The Journal of Dermatology

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Marie Unna hereditary hypotrichosis (MUHH) and multiple familial trichoepithelioma (MFT) are both autosomal dominant disorders. Recently, certain genes (HR and EPS8L3) have been found to be responsible for MUHH, while CYLD has been demonstrated to be the main pathogenic gene in MFT patients. However, there exist a number of CYLD mutation‐negative MFT cases, for which the causative gene has been unknown. Here, we identified a large, five‐generation Han Chinese family with several patients presenting with MUHH and MFT. Sanger sequencing of three genes in 13 family members was performed. We found that the c.1A>G mutation in an inhibitory upstream open‐reading frame of HR (U2HR) was present in all MUHH patients, while no pathogenic variants were found in the 3ʹ‐ or 5ʹ‐untranslated regions, exons or flanking intronic sequences of EPS8L3 or CYLD in any family members. Subsequently, whole‐genome sequencing was performed for five affected and one unaffected family member. We found no CYLD variants but identified an FABP12 variant (rs536105592 G>A) in the patients with both MUHH and MFT. These results suggest that the U2HR mutation was responsible for MUHH and the FABP12 variant may be coincidental in the accompanying MFT in this unique pedigree. This report deepens our understanding of the genetic basis of hair follicle diseases.

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“…Epithelial cells express high levels of PPAR-γ 38 and are involved in colorectal carcinoma development. 39 However, no difference was found in TGF-β protein expression in epithelial cells between mice fed CLA-supplemented and mice fed CT (Supplementary figure 6A). We also investigated epithelial cell-related cytokine mRNAs in sorted epithelial cells from naive mice supplemented with either control or CLA diet and found that CLA supplementation was associated with decreased expression of Tnfa and Tgfb mRNAs, but no difference was observed in Il18 mRNA between cells from control and CLA-fed mice.…”

Section: Cla Supplementation Increases Cacmentioning

confidence: 93%

CLA-supplemented diet accelerates experimental colorectal cancer by inducing TGF-β-producing macrophages and T cells

et al. 2019

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Conjugated linoleic acid (CLA) has been shown to activate the nuclear receptor PPAR-γ and modulate metabolic and immune functions. Despite the worldwide use of CLA dietary supplementation, strong scientific evidence for its proposed beneficial actions are missing. We found that CLA-supplemented diet reduced mucosal damage and inflammatory infiltrate in the dextran sodium sulfate (DSS)-induced colitis model. Conditional deletion of PPAR-γ in macrophages from mice supplemented with CLA diet resulted in loss of this protective effect of CLA, suggesting a PPAR-γ-dependent mechanism mediated by macrophages. However, CLA supplementation significantly worsened colorectal tumor formation induced by azoxymethane and DSS by inducing macrophage and T-cell-producing TGF-β via PPAR-γ activation. Accordingly, either macrophage-specific deletion of PPAR-γ or in vivo neutralization of latency-associated peptide (LAP, a membrane-bound TGF-β)-expressing cells abrogated the protumorigenic effect of CLA. Thus, the anti-inflammatory properties of CLA are associated with prevention of colitis but also with development of colorectal cancer.

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Activation of peroxisome proliferator-activated receptor gamma in mammary epithelial cells upregulates the expression of tumor suppressor Cyld to mediate growth inhibition and anti-inflammatory effects

Cited by 9 publications

References 29 publications

The Tumor Suppressor CYLD Inhibits Mammary Epithelial to Mesenchymal Transition by the Coordinated Inhibition of YAP/TAZ and TGFβ Signaling

The Tumor Suppressor CYLD Inhibits Mammary Epithelial to Mesenchymal Transition by the Coordinated Inhibition of YAP/TAZ and TGFβ Signaling

Marie Unna hereditary hypotrichosis accompanied by multiple familial trichoepithelioma in a Chinese family

CLA-supplemented diet accelerates experimental colorectal cancer by inducing TGF-β-producing macrophages and T cells

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