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

Pseftogas, Athanasios; Xanthopoulos, Konstantinos; Poutahidis, Theofilos; Ainali, Chrysanthi; Dafou, Dimitra; Panteris, Emmanuel; Kern, Joseph G.; Varelas, Xaralabos; Hardas, Alexandros; Gonidas, Christos; Tsingotjidou, Anastasia; Hatzivassiliou, Eudoxia; Mosialos, George

doi:10.3390/cancers12082047

Cited by 12 publications

(13 citation statements)

References 70 publications

(81 reference statements)

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“…As these cells in long-term 3D cultures express markers against both luminal and basal/ME cells and produce laminin-5 to the forming basement membrane ( Figures 2 C and S4 B; See also refs. Debnath et al., 2003 ; Gaiko-Shcherbak et al., 2015 ; Pinto et al., 2011 ; Qu et al., 2015 ; Pseftogas et al., 2020 ), we found this cell line as a useful model to target basal/ME proteins. Similar to canine mammary epithelial cells, loss of CK5, CK14, or α-SMA from human mammary epithelial cell cultures by specific siRNAs led to significantly enlarged mammosphere structures of abnormal morphology ( Figures 2 D and 2E).…”

Section: Resultsmentioning

confidence: 84%

Cytokeratin 5 determines maturation of the mammary myoepithelium

et al. 2021

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Section: Resultsmentioning

confidence: 84%

Cytokeratin 5 determines maturation of the mammary myoepithelium

et al. 2021

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“…CYLD has also, similar to BRD7, been implicated in p53 function as it regulates the p53 DNA damage response (29) and is involved in mammary epithelial-mesenchymal transition (EMT) (30).…”

Section: Resultsmentioning

confidence: 99%

Revisiting the identification of breast cancer tumour suppressor genes defined by copy number loss of the long arm of chromosome 16

Callen

2021

Preprint

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In breast cancer loss of the long-arm of chromosome 16 is frequently observed, suggesting this is the location of tumour suppressor gene or genes. Previous studies localised two or three minimal regions for the LOH genes in the vicinity of 16q22.1 and 16q24.3, however the identification of the relevant tumour suppressor genes has proved elusive. The current availability of large datasets from breast cancers, that include both gene expression and gene dosage of the majority of genes on the long-arm of chromosome 16 (16q), provides the opportunity to revisit the identification of the critical tumour suppressor genes in this region. Utilising such data it was found 37% of breast cancers are single copy for all genes on 16q and this was more frequent in the luminal A and B subtypes. Since luminal breast cancers are associated with a superior prognosis this is consistent with previous data associating loss of 16q with breast cancers of better survival. Previous chromosomal studies found a karyotype with a der t(1;16) to be the basis for a proportion of breast cancers with loss of 16q. Use of data indicating the dosage of genes 21.9% of breast cancers were consistent with a der t(1;16) as the basis for loss of 16q. In such cases there is both loss of one dose of 16q and three doses of 1q suggesting a tumour suppressor function associated with long-arm of chromosome 16 and an oncogene function for 1q. Previous studies have approached the identification of tumour suppressor genes on 16q by utilising breast cancers with partial loss of 16q with the assumption regions demonstrating the highest frequency of loss of heterozygosity pinpoint the location of tumour suppressor genes. Sixty one of 816 breast cancers in this study showed partial loss of 16q defined by dosage of 357 genes. There was no compelling evidence for hot-spots of localised LOH which would pinpoint major tumour suppressor genes. Comparison of gene expression data between various groups of breast cancers based on 16q dosage was used to identify possible tumour suppressor genes. Combining these comparisons, together with known gene functional data, allowed the identification of eleven potential tumour suppressor genes spread along 16q. It is proposed that breast cancers with a single copy of 16q results in the simultaneous reduction of expression of several tumour suppressor genes. The existence of multiple tumour suppressor genes on 16q would severely limit any attempt to pinpoint tumour suppressor genes locations based on localised hot-spots of loss of heterozygosity. Interestingly, the majority of the identified tumour suppressor genes are involved in the modulation of wild-type p53 function. This role is supported by the finding that 80.5% of breast cancers with 16q loss have wild-type p53. TP53 is the most common mutated gene in cancer. In cancers with wild-type p53 would require other strategies to circumvent the key tumour suppressor role of p53. In breast cancers with complete loss of one dose of 16q it is suggested this provides a mechanism that contributes to the amelioration of p53 function.

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“…To what degree MIB2mediated effects on RIPK1 or CYLD signaling contribute to the effects of FAT1 is unknown. An involvement to CYLD in FAT1-dependent regulation of YAP and TAZ appears unlikely, since CYLD downregulation rather correlates with enhanced nuclear localization of YAP/TAZ and increased YAP/TAZ target gene expression 47 . This is supported by our data showing that suppression of FAT1 expression had no effect on CYLD protein levels.…”

Section: Discussionmentioning

confidence: 98%

Endothelial FAT1 inhibits angiogenesis by controlling YAP/TAZ protein degradation via E3 ligase MIB2

Shao

Jin

et al. 2023

Nat Commun

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Activation of endothelial YAP/TAZ signaling is crucial for physiological and pathological angiogenesis. The mechanisms of endothelial YAP/TAZ regulation are, however, incompletely understood. Here we report that the protocadherin FAT1 acts as a critical upstream regulator of endothelial YAP/TAZ which limits the activity of these transcriptional cofactors during developmental and tumor angiogenesis by promoting their degradation. We show that loss of endothelial FAT1 results in increased endothelial cell proliferation in vitro and in various angiogenesis models in vivo. This effect is due to perturbed YAP/TAZ protein degradation, leading to increased YAP/TAZ protein levels and expression of canonical YAP/TAZ target genes. We identify the E3 ubiquitin ligase Mind Bomb-2 (MIB2) as a FAT1-interacting protein mediating FAT1-induced YAP/TAZ ubiquitination and degradation. Loss of MIB2 expression in endothelial cells in vitro and in vivo recapitulates the effects of FAT1 depletion and causes decreased YAP/TAZ degradation and increased YAP/TAZ signaling. Our data identify a pivotal mechanism of YAP/TAZ regulation involving FAT1 and its associated E3 ligase MIB2, which is essential for YAP/TAZ-dependent angiogenesis.

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

Cited by 12 publications

References 70 publications

Cytokeratin 5 determines maturation of the mammary myoepithelium

Cytokeratin 5 determines maturation of the mammary myoepithelium

Revisiting the identification of breast cancer tumour suppressor genes defined by copy number loss of the long arm of chromosome 16

Endothelial FAT1 inhibits angiogenesis by controlling YAP/TAZ protein degradation via E3 ligase MIB2

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