Lack of IRF6 Disrupts Human Epithelial Homeostasis by Altering Colony Morphology, Migration Pattern, and Differentiation Potential of Keratinocytes

Girousi, Eleftheria; Muerner, Lukas; Parisi, Lucia; Rihs, Silvia; Gunten, Stephan von; Katsaros, Christos; Degen, Martin

doi:10.3389/fcell.2021.718066

Cited by 6 publications

(10 citation statements)

References 62 publications

(98 reference statements)

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“…Forced expression of IRF6 and GRHL3 in SCC-68 was not only associated with a partial reversal of the EMT, but also with a reduced migratory capacity as evidenced by a delay in closing of a scratch in vitro (Figure 3F). While these results are in agreement with results in other cancers for IRF6 and GRHL3 (19, 46, 48), epithelial cell migration in healing wounds as well as of normal keratinocytes seem to depend on the presence of IRF6 and GRHL3 (41,(49)(50)(51). However, we did not observe any differences in the migration pattern between SCC-68 control and IRF6 and GRHL3 overexpressing cells (Supplementary Movies 1-3).…”

Section: Discussionsupporting

confidence: 92%

“…However, we did not observe any differences in the migration pattern between SCC-68 control and IRF6 and GRHL3 overexpressing cells (Supplementary Movies 1-3). Such differences have been reported in Irf6 -/keratinocytes and in IRF6 depleted human keratinocytes that showed less directionality (49) and preferentially moved as single cells and not as continuous epithelial cell sheet (41), respectively. In the breast cancer cell line T47D, elevated IRF6 and GRHL3 did not modulate EMT marker expression (Figure 3D).…”

Section: Discussionsupporting

confidence: 53%

“…Both IRF6 and GRHL3 have been found to be implicated in regulating EMT during development as well as in cancer progression ( 39 – 41 ). Therefore, we wished to know whether elevated IRF6 and GRHL3 levels in T47D and SCC-68 were able to modulate the expression levels of typical EMT-related markers.…”

Section: Resultsmentioning

confidence: 99%

“…The role of IRF6 in impairing EMT in cancer cells contradicts what is known about its physiological function. Overexpression of IRF6 increased SNAIL2, an important mediator of EMT, during palatogenesis in mice ( 40 ) and a more recent study in human postnatal keratinocytes revealed that EMT is dependent on IRF6, but that the epithelial cell characteristics are maintained even in the absence of IRF6 ( 41 ). In contrast, GRHL3 has been reported to play an important role during MET, the reversion of the EMT process ( 47 ), which fits to our data in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…Our data provide evidence that poor SCC cell differentiation might be a consequence of reduced IRF6 and GRHL3 levels. Notable, a direct role of IRF6 in regulating K10 has been recently shown in IRF6 knock-out keratinocytes by proteomics ( 41 ). Since the differentiation status often predicts patient survival in SCCs ( 2 ), IRF6 and GRHL3 levels might represent valuable prognostic and/or differentiation-defining biomarkers in SCCs.…”

Section: Discussionmentioning

confidence: 99%

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Consistent downregulation of the cleft lip/palate-associated genes IRF6 and GRHL3 in carcinomas

Parisi

Mockenhaupt²,

Rihs³

et al. 2022

Front. Oncol.

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Interferon Regulatory Factor 6 (IRF6) and Grainyhead Like Transcription Factor 3 (GRHL3) are transcription factors that orchestrate gene regulatory networks required for the balance between keratinocyte differentiation and proliferation. Absence of either protein results in the lack of a normal stratified epidermis with keratinocytes failing to stop proliferating and to terminally differentiate. Numerous pathological variants within IRF6 and GRHL3 have been identified in orofacial cleft-affected individuals and expression of the two transcription factors has been found to be often dysregulated in cancers. However, whether orofacial cleft-associated IRF6 and GRHL3 variants in patients might also affect their cancer risk later in life, is not clear yet. The fact that the role of IRF6 and GRHL3 in cancer remains controversial makes this question even more challenging. Some studies identified IRF6 and GRHL3 as oncogenes, while others could attribute tumor suppressive functions to them. Trying to solve this apparent conundrum, we herein aimed to characterize IRF6 and GRHL3 function in various types of carcinomas. We screened multiple cancer and normal cell lines for their expression, and subsequently proceeded with functional assays in cancer cell lines. Our data uncovered consistent downregulation of IRF6 and GRHL3 in all types of carcinomas analyzed. Reduced levels of IRF6 and GRHL3 were found to be associated with several tumorigenic properties, such as enhanced cell proliferation, epithelial mesenchymal transition, migration and reduced differentiation capacity. Based on our findings, IRF6 and GRHL3 can be considered as tumor suppressor genes in various carcinomas, which makes them potential common etiological factors for cancer and CLP in a fraction of CLP-affected patients.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 53%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Consistent downregulation of the cleft lip/palate-associated genes IRF6 and GRHL3 in carcinomas

Parisi

Mockenhaupt²,

Rihs³

et al. 2022

Front. Oncol.

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Neural crest and periderm-specific requirements ofIrf6during neural tube and craniofacial development

Carroll,

Schafer,

Dalessandro

et al. 2024

Preprint

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IRF6is a key genetic determinant of syndromic and non-syndromic cleft lip and palate. The ability to interrogate post-embryonic requirements ofIrf6has been hindered, as globalIrf6ablation in the mouse causes neonatal lethality. Prior work analyzingIrf6in mouse models defined its role in the embryonic surface epithelium and periderm where it is required to regulate cell proliferation and differentiation. Several reports have also describedIrf6gene expression in other cell types, such as muscle, and neuroectoderm. However, analysis of a functional role in non-epithelial cell lineages has been incomplete due to the severity and lethality of theIrf6knockout model and the paucity of work with a conditionalIrf6allele. Here we describe the generation and characterization of a newIrf6floxed mouse model and analysis ofIrf6ablation in periderm and neural crest lineages. This work found that loss ofIrf6in periderm recapitulates a mildIrf6null phenotype, suggesting thatIrf6-mediated signaling in periderm plays a crucial role in regulating embryonic development. Further, conditional ablation ofIrf6in neural crest cells resulted in an anterior neural tube defect of variable penetrance. The generation of this conditionalIrf6allele allows for new insights into craniofacial development and new exploration into the post-natal role ofIrf6.

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High incidence and geographic distribution of cleft palate cases in Finland are associated with a regulatory variant inIRF6

Rahimov,

Nieminen,

Kumari

et al. 2024

Preprint

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In Finland the frequency of isolated cleft palate (CP) is higher than that of isolated cleft lip with or without cleft palate (CL/P). This trend contrasts to that in other European countries but its genetic underpinnings are unknown. We performed a genome-wide association study for orofacial clefts, which include CL/P and CP, in the Finnish population. We identified rs570516915, a single nucleotide polymorphism that is highly enriched in Finns and Estonians, as being strongly associated with CP (P= 5.25 × 10−34, OR = 8.65, 95% CI 6.11–12.25), but not with CL/P (P= 7.2 × 10−5), with genome-wide significance. The risk allele frequency of rs570516915 parallels the regional variation of CP prevalence in Finland, and the association was replicated in independent cohorts of CP cases from Finland (P= 8.82 × 10−28) and Estonia (P= 1.25 × 10−5). The risk allele of rs570516915 disrupts a conserved binding site for the transcription factor IRF6 within a previously characterized enhancer upstream of theIRF6gene. Through reporter assay experiments we found that the risk allele of rs570516915 diminishes the enhancer activity. Oral epithelial cells derived from CRISPR-Cas9 edited induced pluripotent stem cells demonstrate that the CP-associated allele of rs570516915 concomitantly decreases the binding of IRF6 and the expression level ofIRF6, suggesting impairedIRF6autoregulation as a molecular mechanism underlying the risk for CP.

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Lack of IRF6 Disrupts Human Epithelial Homeostasis by Altering Colony Morphology, Migration Pattern, and Differentiation Potential of Keratinocytes

Cited by 6 publications

References 62 publications

Consistent downregulation of the cleft lip/palate-associated genes IRF6 and GRHL3 in carcinomas

Consistent downregulation of the cleft lip/palate-associated genes IRF6 and GRHL3 in carcinomas

Neural crest and periderm-specific requirements ofIrf6during neural tube and craniofacial development

High incidence and geographic distribution of cleft palate cases in Finland are associated with a regulatory variant inIRF6

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