Serine and arginine-rich splicing factor 3 regulates epidermal differentiation in cutaneous squamous cell carcinoma

Summary: Abstract Body: Serine/Arginine-rich splicing factor 3 (SRSF3) is one of 12 SRSFs that regulate gene expression via alternative splicing. SRSF3 overexpression is associated with the progression of many different solid malignancies. However, SRSF3 expression in keratinocyte cancers remains uncharacterized and the role of this protein in the skin is unknown. Analysis of RNA-seq data from 279 human skin tissues revealed upregulation of SRSF3 in cutaneous squamous cell carcinoma (cSCC) compared to normal skin. This was mirrored by higher expression of SRSF3 in squamous cancer cell lines in relation to normal primary human keratinocytes. Reduction of SRSF3 with a specific inhibitor, SFI003, resulted in enhanced epidermal differentiation in vitro as well as in skin organoid models, with induction of both early (MAF, KRT1) and late (IVL, FLG, LCE3D, CASP14) differentiation markers. Our data suggests that in cSCC, SRSF3 overexpression suppresses cellular differentiation to enable cancer progression. In a clinical setting, patients taking known SRSF3 inhibitors digoxin (n=4,149) and amiodarone (n=9,579) exhibited higher cSCC-free survival compared to a propensity score-matched cohort treated with beta blockers (n=100,000; down sampled). The adjusted hazard ratios (HR) for digoxin (0.57, 95% CI 34-95%) and amiodarone (0.59, 95% CI 40-87%) revealed a lower risk of developing cSCC. Thus, SRSF3 upregulation may be a novel therapeutic target in cSCC that can improve patient prognoses. Isoline Donohue¹, Haiyin He², Audrey Nguyen¹, Gavin Hui^{3, 4}, Jananee Muralidharan³, William Pike³, Michael Jackson³, Christine Ko⁵, Ankit Srivastava¹, Carolyn Lee^{1, 6} 1. Dermatology, Stanford University, Stanford, CA, United States. 2. Peking University, Beijing, Beijing, China. 3. Atropos Health, New York, NY, United States. 4. Department of Hematology & Oncology, University of California Los Angeles, Los Angeles, CA, United States. 5. Departments of Dermatology and Pathology, Yale University, New Haven, CT, United States. 6. Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA, United States. UV Biology/Injury and Non-melanoma Cancers