Novel Tumor Suppressive Role of the RAS GTPase-Activating Protein RASA5 to RAS Signaling Perturbation in Human Carcinomas

Abstract

RAS activation is common in human cancers with even few mutations of Ras, indicating alternative regulation leading to aberrant activation of RAS signaling. We identified a Ras GTPase-activating protein gene RASA5/SYNGAP, located at a common 6p21.3 deletion, being methylated and downregulated in several carcinomas, while other RASA family members (RASA1-4) were broadly expressed and only occasionally downregulated in tumors, indicating that RASA5 has a unique and important role in tumorigenesis among RASA family. Unlike other RASA members like RASA1, mutations are rare for RASA5, while its promoter CpG methylation is frequent in cell lines and primary carcinomas of esophageal, nasopharyngeal, breast, lung, gastric and colon, and associated with patient poor survival. We further found that RASA5 inhibited tumor cell migration/invasion, and growth in mouse model, thus as a tumor suppressor. RASA5 suppressed RAS signaling, depending on its RasGAP catalytic activity, which could be counteracted by oncogenic HRas Q61L mutant. Meanwhile, RASA5 knockdown enhanced Ras signaling to promote tumor cell growth. RASA5 also inhibited epithelial-mesenchymal transition through regulating actin remodeling. Thus, our study characterized a novel tumor suppressive role of RASA5, in addition to its known functions in neuro cell regulation. Epigenetic inactivation of RASA5 contributing to hyperactive RAS signaling might have an important role in Ras-driven oncogenesis, particularly in carcinomas with few oncogenic Ras mutations.

Keywords: RASA5, RasGAP, Ras, tumor suppressor, methylation