Down-regulation of the Tumor Suppressor CYLD Enhances the Transformed Phenotype of Human Breast Cancer Cells

Orfanidou, Timoklia; Xanthopoulos, Konstantinos; Dafou, Dimitra; Pseftogas, Athanasios; Hadweh, Paul; Psyllaki, Claire; Hatzivassiliou, Eudoxia; Mosialos, George

doi:10.21873/anticanres.11717

Cited by 6 publications

(3 citation statements)

References 7 publications

(12 reference statements)

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“…The effects of CYLD deficiency and overexpression in breast cancer cell lines have suggested important tumor suppressive roles [ 33 , 34 , 35 ]. To gain insight into the tumor suppressive roles of CYLD in mammary epithelium, we used CRISPR/Cas9 to generate clones of non-transformed MCF10A cells that possess different mutations in the CYLD gene, which result in the loss of full-length CYLD protein ( Figure 1 a) and reduction of CYLD mRNA expression ( Figure 1 b) that is likely due to non-sense mRNA decay (NMD).…”

Section: Resultsmentioning

confidence: 99%

“…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%

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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: Resultsmentioning

confidence: 99%

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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“…CYLD expression is repressed in breast cancer tissues and functions as an independent prognostic index [51]. CYLD inhibits breast cancer growth by negatively modulating the NF-κB pathway and targeting several regulators of NF-κB via deubiquitinase activity [52]. For example, CYLD removes ubiquitin chains from TRAF2, which is necessary for activating IKK, a central component to sustain NF-κB signaling [53].…”

Section: Other Dubs In Breast Cancer Growthmentioning

confidence: 99%

Roles and Mechanisms of Deubiquitinases (DUBs) in Breast Cancer Progression and Targeted Drug Discovery

Zhang

Wei

2021

Life

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Deubiquitinase (DUB) is an essential component in the ubiquitin—proteasome system (UPS) by removing ubiquitin chains from substrates, thus modulating the expression, activity, and localization of many proteins that contribute to tumor development and progression. DUBs have emerged as promising prognostic indicators and drug targets. DUBs have shown significant roles in regulating breast cancer growth, metastasis, resistance to current therapies, and several canonical oncogenic signaling pathways. In addition, specific DUB inhibitors have been identified and are expected to benefit breast cancer patients in the future. Here, we review current knowledge about the effects and molecular mechanisms of DUBs in breast cancer, providing novel insight into treatments of breast cancer-targeting DUBs.

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CYLD induces high oxidative stress and DNA damage through class I HDACs to promote radiosensitivity in nasopharyngeal carcinoma

Li,

Yang,

Xie

et al. 2024

Cell Death Dis

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Abnormal expression of Cylindromatosis (CYLD), a tumor suppressor molecule, plays an important role in tumor development and treatment. In this work, we found that CYLD binds to class I histone deacetylases (HDAC1 and HDAC2) through its N-terminal domain and inhibits HDAC1 activity. RNA sequencing showed that CYLD-HDAC axis regulates cellular antioxidant response via Nrf2 and its target genes. Then we revealed a mechanism that class I HDACs mediate redox abnormalities in CYLD low-expressing tumors. HDACs are central players in the DNA damage signaling. We further confirmed that CYLD regulates radiation-induced DNA damage and repair response through inhibiting class I HDACs. Furthermore, CYLD mediates nasopharyngeal carcinoma cell radiosensitivity through class I HDACs. Thus, we identified the function of the CYLD-HDAC axis in radiotherapy and blocking HDACs by Chidamide can increase the sensitivity of cancer cells and tumors to radiation therapy both in vitro and in vivo. In addition, ChIP and luciferase reporter assays revealed that CYLD could be transcriptionally regulated by zinc finger protein 202 (ZNF202). Our findings offer novel insight into the function of CYLD in tumor and uncover important roles for CYLD-HDAC axis in radiosensitivity, which provide new molecular target and therapeutic strategy for tumor radiotherapy.

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Down-regulation of the Tumor Suppressor CYLD Enhances the Transformed Phenotype of Human Breast Cancer Cells

Abstract: Abstract. Background

Cited by 6 publications

References 7 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

Roles and Mechanisms of Deubiquitinases (DUBs) in Breast Cancer Progression and Targeted Drug Discovery

CYLD induces high oxidative stress and DNA damage through class I HDACs to promote radiosensitivity in nasopharyngeal carcinoma

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