RASD2 promotes the development and metastasis of uveal melanoma via enhancing glycolysis

Abstract

Uveal melanoma (UVM) is a primary intraocular tumor in adults with high mortality. Nearly half of primary UVM tumors metastasize to the liver and lung. RASD2 encodes a Ras-related GTP-binding protein and involves in psychiatric disorders. RASD2 has been shown to be expressed in multiple tissues including skin. However, the function of RASD2 in UVM is not fully studied. Here, we investigated the expression, functional role and expression regulation of RASD2 in UVM. RASD2 expression was significantly elevated in metastasis UVM, while high level of RASD2 indicated poor prognosis of patients with metastasis UVM. Silencing RASD2 dampened cell growth, migration and invasion of UVM cells. Additionally, xenograft tumor model suggested that RASD2 knockdown suppressed in vivo UVM xenograft tumor growth and lung metastasis. Bioinformatics analysis predicted that RASD2 regulated epithelial-mesenchymal transition and glycolysis in UVM, which was further confirmed both in vivo and in vitro. Moreover, RASD2 knockdown suppressed UVM cell metabolism, with decreased expression of glycolysis-related HK2, LDHA, GLUT1 and PKM2. In addition, we demonstrated that PKM2 knockdown antagonized the effect of RASD2 on cell growth, migration and invasion. In summary, our findings suggest that RASD2 may enhance the development and metastasis of UVM via enhancing glycolysis. Targeting RASD2 could be a novel therapeutic strategy for UVM treatment.