Tumor Suppression of Ras GTPase-Activating Protein RASA5 through Antagonizing Ras Signaling Perturbation in Carcinomas
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
Affiliations
Lili Li
Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong; Corresponding author
Yichao Fan
Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong
Xin Huang
Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong
Jie Luo
Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong
Lan Zhong
Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong
Xing-sheng Shu
Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong; School of Medicine and Institute of Molecular Medicine, Shenzhen University, Shenzhen, China
Li Lu
Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong
Tingxiu Xiang
Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
Anthony T.C. Chan
Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong
Winnie Yeo
Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong
Ceshi Chen
Key Laboratory of Animal Models and Human Disease Mechanisms of CAS and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
Wai Yee Chan
School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong
Richard L. Huganir
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Qian Tao
Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong; Corresponding author
Summary: 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. : Biological Sciences; Molecular Biology; Cell Biology; Cancer Subject Areas: Biological Sciences, Molecular Biology, Cell Biology, Cancer