Empty spiracles homeobox 2 (EMX2) transcription factor functions as a tumor suppressor in renal cell carcinoma by targeting CADM1

Abstract Renal cell carcinoma (RCC), a prevalent urinary system malignancy, often metastasizes at an early stage. Characterized by a complex pathogenesis and high mortality rate, RCC poses a significant clinical challenge. We evaluated the expression level of EMX2 in RCC patients and revealed a significant reduction of EMX2 expression, correlating with poor RCC patient prognosis. EMX2 functions as a tumor suppressor and inhibits RCC cell proliferation and migration, accompanied by programmed cell death. Implantation of EMX2-transduced RCC cells beneath the mouse kidney capsule or subcutaneous injection of transduced RCC cells results in a reduction in tumor growth and size. Through RNA-seq and chromatin immunoprecipitation sequencing analyses, we have identified Cell Adhesion Molecule 1 (CADM1) as a direct transcriptional target of EMX2's suppressive effects. CADM1 induction by EMX2 triggers PARP1-mediated parthanatos, a specific type of cell death due to mitochondrial oxidation reduction, in migrating RCC cells. Concurrently, EMX2-CADM1 upregulation instigates Caspase-3-dependent apoptosis in attached RCC cells. Furthermore, EMX2-CADM1 transcriptional axis also inhibits the PI3K-AKT pathway to impair RCC cell growth. Hence, the orchestrated effects mediated by EMX2-CADM1 axis promote RCC cell death and suppresse its growth and invasion, providing potential intervention strategies for combating RCC. Implications: The EMX2-CADM1 transcriptional axis offers a promising therapeutic target for inducing cell death and inhibiting growth and invasion in renal cell carcinoma, which could lead to more effective treatment strategies for this aggressive malignancy.