PHF20 stabilizes the GAS7-F-actin axis to drive DNA damage repair and chemoresistance in cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (cSCC) is a common and aggressive skin cancer, with treatment options for advanced stages often limited by chemoresistance. Here, we observe a positive correlation between PHF20 expression and the malignancy and tumor grade of cSCC. Functional studies suggest that PHF20 promotes oncogenic phenotypes, including proliferation, invasion, and epithelial-mesenchymal transition. Notably, PHF20 depletion appears to sensitize cSCC cells to chemotherapeutic agents. Mechanistically, we show that PHF20 interacts with and promotes the ubiquitin-mediated degradation of GAS7. This downregulation of GAS7 is associated with nuclear F-actin assembly, a process that has been implicated in DNA damage repair (DDR). Consequently, PHF20 loss stabilizes GAS7, enhances nuclear F-actin assembly, and is accompanied by increased DNA damage accumulation. These in vitro findings were corroborated in vivo, where PHF20 knockdown suppressed tumor growth and increased DNA damage. Together, PHF20 may contribute to the regulation of DDR and chemotherapeutic response, highlighting its potential as a therapeutic target in poorly differentiated cSCC.