VGLL4 Suppresses Malignant Phenotypes of Clear Cell Renal Cell Carcinoma Cells Through Modulation of Hippo/YAP and Wnt/β-Catenin Signaling Pathways

Abstract

Background/Objectives: Clear cell renal cell carcinoma (ccRCC), the most common and aggressive subtype of kidney cancer, continues to face challenges in early diagnosis and treatment, driving the need for reliable biomarkers and therapeutic targets. Vestigial-like family member 4 (VGLL4), a transcriptional cofactor, has been identified as a tumor suppressor in several malignancies. However, its clinical significance, biological functions, and underlying mechanisms in ccRCC remain largely unknown. Methods: In this study, we examined VGLL4 expression in ccRCC and normal tissues at both mRNA and protein levels and analyzed its correlation with clinicopathological features and patient prognosis. Functional experiments were performed to evaluate the effects of VGLL4 overexpression on ccRCC cell proliferation, migration, and invasion in vitro, as well as tumor growth in vivo. Integrated transcriptomic profiling and immunoblot validation were employed to explore the underlying signaling pathways. Results: We found that VGLL4 was downregulated in ccRCC tissues compared to normal counterparts at both mRNA and protein levels, and its low expression correlates with advanced disease stage and poorer overall survival. Functional experiments demonstrated that VGLL4 overexpression significantly suppressed the proliferation, migration, and invasion of ccRCC cells in vitro and effectively hindered tumor growth in vivo. Mechanistically, integrated transcriptomic profiling and immunoblot validation suggest that the tumor-suppressive effects of VGLL4 are mediated through the coordinated modulation of the Hippo/YAP and Wnt/β-catenin signaling pathways, at least in part by attenuating the activation and transcriptional activities of YAP and β-catenin. Conclusions: Collectively, these findings establish VGLL4 as a tumor suppressor in ccRCC and highlight its potential as a prognosis-related biomarker and candidate therapeutic target through its dual regulatory role in Hippo/YAP and Wnt/β-catenin signaling cascades.