The human Flower isoform hFWE4 facilitates cornification in cutaneous squamous cell carcinoma

Arising from epidermal keratinocytes, cutaneous squamous cell carcinoma (cSCC) is the second most common human tumor. Transformed keratinocytes in cSCC retain partial ability to execute terminal-differentiation, forming keratinized, cyst-like structures called 'keratin pearls' rather than normal stratified epidermis. It is readily appreciated that well-differentiated tumors have better prognosis than poorly differentiated ones; however, molecular mechanisms governing terminal differentiation in cSCC remain incompletely understood. Delineating these mechanisms promises to identify additional differentiation-associated molecules that could serve as histologic markers for prognostic stratification. In this study, we demonstrate that FWE (Flower), a newly described regulator of lamellar body trafficking in normal epidermis, is specifically expressed in highly differentiated cSCC layers. Genetic knockout of FWE dysregulates cornification and lamellar body-related gene expression, causing abnormal keratinization, whereas ectopic hFWE4 expression drives G1 arrest and exit from the proliferative basal keratinocyte population. Poorly differentiated human cSCC exhibit minimal FWE positivity, whereas well-differentiated regions show readily detectable FWE. We propose that, as in normal epidermis, FWE facilitates late stages of cornification in cSCC and represents a differentiation marker that can classify differentiation status to improve prognostic stratification of these tumors.