Tumor Suppression of Ras GTPase-Activating Protein RASA5 through Antagonizing Ras Signaling Perturbation in Carcinomas.

Abstract

Aberrant RAS signaling activation is common in cancers with even few Ras mutations, indicating alternative dysregulation other than genetic mutations. We identified a Ras GTPase-activating gene RASA5/SYNGAP1, at the common 6p21.3 deletion, methylated/downregulated in multiple carcinomas and different from other RASA family members (RASA1-RASA4), indicating its special functions in tumorigenesis. RASA5 mutations are rare, unlike other RASA members, whereas its promoter CpG methylation is frequent in multiple cancer cell lines and primary carcinomas and associated with patient's poor survival. RASA5 expression inhibited tumor cell migration/invasion and growth in mouse model, functioning as a tumor suppressor. RASA5 suppressed RAS signaling, depending on its Ras GTPase-activating protein catalytic activity, which could be counteracted by oncogenic HRas Q61L mutant. RASA5 knockdown enhanced Ras signaling to promote tumor cell growth. RASA5 also inhibited epithelial-mesenchymal transition (EMT) through regulating actin reorganization. Thus, epigenetic inactivation of RASA5 contributing to hyperactive RAS signaling is involved in Ras-driven human oncogenesis.

• Authors: Lili Li, Yichao Fan, Xin Huang, Jie Luo, Lan Zhong, Xing-Sheng Shu, Li Lu, Tingxiu Xiang, Anthony T C Chan, Winnie Yeo, Ceshi Chen, Wai Yee Chan, Richard L Huganir, Qian Tao
• Journal: iScience (iScience) Vol. 21 Pg. 1-18 (Nov 22 2019) ISSN: 2589-0042 [Electronic] United States
• PMID: 31654850 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.