Silencing GRHL3 promotes multiple organ distant metastasis of lung squamous cell carcinoma cells by enhancing SOX2 stability via SIRT1

Abstract Aberrant expression of grainyhead‐like transcription factor 3 (GRHL3) has been extensively reported in the development and progression of several squamous cell carcinomas, such as cutaneous, head and neck, and esophageal squamous cell carcinoma. However, the clinical significance and biological roles of GRHL3 in lung squamous cell (LUSC) carcinoma are largely unclear. Herein, we report that GRHL3 was significantly upregulated in lung squamous epithelium of LUSC tissues, bronchiole, and bronchus. Moreover, expression levels of GRHL3 were decreased with the advance of pathological grade, and low GRHL3 level presented poor overall survival and short progression‐free and distant metastasis‐free survival in LUSC patients but had no prognostic significance in LUAD patients. Functional experiments in vivo showed that downregulating GRHL3 promoted not only lung colonization and growth but also multiple organ distant metastasis of LUSC cells, including bone, brain, and liver. Moreover, silencing GRHL3 promoted anoikis resistance and cancer stem cell (CSCs) characteristics of LUSC cells in vitro . Mechanistically, silencing GRHL3 stabilized SOX2 via SIRT1‐mediated decreasing acetylation and subsequent ubiquitination‐dependent degradation in LUSC cells. Thus, in‐depth understanding of the underlying mechanism of GRHL3 in the progression of LUSC will facilitate the development of prognostic biomarker and therapeutic avenues against LUSC, which will present favorable prospects in improving outcomes of LUSC patients. © 2025 The Pathological Society of Great Britain and Ireland.