Empty Spiracles Homeobox 2 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 empty spiracles homeobox 2 (EMX2) in patients with RCC and revealed a significant reduction of EMX2 expression, correlating with a poor prognosis in patients with RCC. 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 sequencing 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, the EMX2–CADM1 transcriptional axis also inhibits the PI3K–AKT pathway to impair RCC cell growth. Hence, the orchestrated effects mediated by the EMX2–CADM1 axis promote RCC cell death and suppress 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 RCC, which could lead to more effective treatment strategies for this aggressive malignancy.