Interplay of ELF5, GATA-3 and FLI-1 regulate malignant transformation of keratinocytes

Sep 22, 2026

Cutaneous squamous cell carcinoma originates from epidermal keratinocytes, yet the mechanisms blocking complete keratinocyte differentiation are unclear. This study shows ELF5 is abundantly expressed in healthy human skin but lost in cSCC biopsies. CRISPR-Cas9 knockout decreases keratinocyte differentiation and increases migration and tumorigenicity in vitro, while ELF5 overexpression inhibits migration and proliferation. RNA transcriptomics identify GATA-3 and FLI-1 as key ELF5 targets, supporting a role for ELF5 in preventing keratinocyte transformation and suppressing tumorigenesis.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages18

Reading Time45 min

AccessFree to download

Background

ELF5 expression in health and cSCC

Functional effects in keratinocytes

Transcriptomic identification of targets

Implications and future directions

[www. nature.com/scientificreports](www. nature.com/scientificreports) OPEN Interplay of ELF5, GATA-3 and FLI-1 regulate malignant transformation of keratinocytes Hetal. J. Patel1, Maximilian. E. Pickup1,2, Maryam. A. Lawal1, Chandrakala Khadka1 & Mohammed. I. Ahmed1 Cutaneous squamous cell carcinoma (cSCC) arises from epidermal keratinocytes and is the second most common epithelial malignancy. E74-like factor 5 (ELF5) is a member of the epithelium specific ETS subfamily of transcription factors and is essential for epithelial development, homeostasis and prevention of epithelial tumourigenesis. Transformation of keratinocytes involves the disruption of the progenitor differentiation program causing keratinocytes to fail to complete the process. This can lead to dysplastic epithelium and precancerous cells in skin. However, the precise mechanisms that causes the failure of keratinocytes to differentiate completely is not well understood. In our study, we discovered that ELF5 is abundantly expressed in healthy human skin (both basal and suprabasal layers), while its expression is lost in cSCC tissue biopsies. Using CRISPR-Cas9 knockout technology, functional studies along with transcript and protein analysis, loss of ELF5 in immortalised healthy keratinocytes leads to decreased ability of cells to differentiation and increased migration and tumourigenicity, in vitro. Overexpression of ELF5 leads to inhibition of cell migration and proliferation in keratinocytes and in cancer cell lines (A431 and SCC-9), in vitro. Further analysis using RNA transcriptomics has uncovered that GATA-3 and FLI-1 are potentially key molecular targets of ELF5 in keratinocytes. ELF5 regulation of both GATA-3 and FLI-1 is required to maintain the balance between healthy keratinocytes (proliferation/differentiation) and to inhibit precancerous cell formation (tumourigenicity) . Our data indicates that ELF5 plays an important role in potentially preventing transformation of keratinocytes and could suppresses skin tumourigenesis. However, additional studies are required to determine this, which could lead the targeting of ELF5 for future drug treatments in cSCC. Better understanding of the underlying mechanisms by which ELF5 regulates gene expression and consequently cell activity will provide new knowledge that can be translated into long-term benefits for patients with precancerous lesions to cSCC. Keywords ELF5, Keratinocytes, Proliferation, Differentiation, cSCC Cutaneous squamous cell carcinoma (cSCC) arises from epidermal keratinocytes and is the second most common epithelial malignancy1, with an annual incidence of more than 1 million in the USA1 and over 45,000 incidences every year in England2. The global age-standardised prevalence of cSCC was 39.29 per 100 000 population, the highest among the three common skin cancers, including malignant skin melanoma (25.97 per 100 000 population) and basal cell carcinoma (5.15 per 100 000 population)3,4. The stepwise progression from healthy epidermal keratinocytes to precancerous lesions and subsequent cSCC involves mutations in pathways that govern cell division, intercommunication, apoptosis and differentiation5. Transformation of keratinocytes disrupts the progenitor differentiation program causing keratinocytes in cSCC formation to fail to complete the differentiation process, leading to precancerous cells and dysplastic skin epithelium. However, the precise mechanisms that causes the failure of keratinocytes to differentiate completely is not well understood. E74-like factor 5 (ELF5) is a member of the E26 transformation specific (ETS) family of transcription factors, which is expressed predominantly in epithelial cells and has been shown to be a critical transcriptional regulator of cell fate in stem/progenitor cells by regulating target genes, such as, BMP and Notch signalling pathways6–9, which are involved in cell proliferation and differentiation processes in development of epithelia

FAQs

What is the role of ELF5 in healthy skin versus cSCC?

ELF5 is abundantly expressed in healthy human skin but its expression is lost in cSCC tissue biopsies.

How does knocking out ELF5 affect keratinocytes in vitro?

Loss of ELF5 decreases the ability of keratinocytes to differentiate and increases migration and tumorigenicity in vitro.

Which molecular targets does transcriptomics suggest ELF5 regulates in keratinocytes?

RNA transcriptomics suggests GATA-3 and FLI-1 are key molecular targets of ELF5.

Sep 22, 2026

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