LncRNA MAGI2-AS3 inhibits tumor progression and angiogenesis by regulating ACY1 via interacting with transcription factor HEY1 in clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) represents the most common type of RCC in adults, characterized by hyper-vascularization and metastatic relapse. Surgical resection is the main treatment due to poor response of ccRCC to radio-and chemotherapy. However, the high complexity of tumor vasculature in ccRCC has thwarted effects to develop new therapeutic strategies for ccRCC. In this study, we identify the anti-angiogenic activity of MAGI2-AS3 in ccRCC. 86 paired samples of tumor tissues and adjacent no-tumor tissues were collected from ccRCC patients. Dual-luciferase reporter assay, RIP, and ChIP assays were employed to confirm interactions between MAGI2-AS3, transcription factor HEY1, and the ACY1 gene. In other studies, we assayed human ccRCC cells RLC-310 for their viability, migration and invasion using CCK-8 detection and transwell chamber systems. Angiogenesis was evaluated in the Matrigel-based human umbilical vein endothelial cell (HUVEC)-RLC-310 coculture model and immunohistochemical staining for vascular endothelial growth factor (VEGF) and CD31 in tumor tissues collected from a xenograft ccRCC mouse model. MAGI2-AS3 and ACY1 expression was downregulated in ccRCC tissues, and low expression of MAGI2-AS3 was associated with poor patient survival. Overexpression of MAGI2-AS3 could reduce ccRCC cell viability and migration, inhibit vessel-like tube formation of HUVECs in vitro, and repress tumor growth and angiogenesis in vivo. MAGI2-AS3 bound with HEY1 and reduced the HEY1 enrichment at the ACY1 promoter region, thus increasing ACY1 gene transcription. HEY1 knockdown or ACY1 overexpression that resisted MAGI2-AS3 knockdown was found in the in vivo and in vitro settings. The present study demonstrates that MAGI2-AS3 exerts tumor-suppressive, anti-angiogenic activities in ccRCC by modulating the HEY1/ACY1 pathway, thus lending support for conducting further investigations of anti-angiogenesis therapy for ccRCC.