ETS1-mediated Regulation of SOAT1 Enhances the Malignant Phenotype of Oral Squamous Cell Carcinoma and Induces Tumor-associated Macrophages M2-like Polarization

Abstract

Oral squamous cell carcinoma (OSCC) is an aggressive cancer that poses a substantial threat to human life and quality of life globally. Lipid metabolism reprogramming significantly influences tumor development, affecting not only tumor cells but also tumor-associated macrophages (TAMs) infiltration. <i>SOAT1</i>, a critical enzyme in lipid metabolism, holds high prognostic value in various cancers. This study revealed that <i>SOAT1</i> is highly expressed in OSCC tissues and positively correlated with M2 TAMs infiltration. Increased <i>SOAT1</i> expression enhanced the capabilities of cell proliferation, tumor sphere formation, migration, and invasion in OSCC cells, upregulated the SREBP1-regulated adipogenic pathway, activated the PI3K/AKT/mTOR pathway and promoted M2-like polarization of TAMs, thereby contributing to OSCC growth both <i>in vitro</i> and <i>in vivo</i>. Additionally, we explored the upstream transcription factors that regulate <i>SOAT1</i> and discovered that <i>ETS1</i> positively regulates <i>SOAT1</i> expression levels. Knockdown of <i>ETS1</i> effectively inhibited the malignant phenotype of OSCC cells, whereas restoring <i>SOAT1</i> expression significantly mitigated this suppression. Based on these findings, we suggest that <i>SOAT1</i> is regulated by <i>ETS1</i> and plays a pivotal role in the development of OSCC by facilitating lipid metabolism and M2-like polarization of TAMs. We propose that <i>SOAT1</i> is a promising target for OSCC therapy with tremendous potential.