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

50 Pages Posted: 25 Mar 2019 Sneak Peek Status: Published

See all articles by Lili Li

Lili Li

The Chinese University of Hong Kong, Li Ka Shing Inst. of Health Sciences, Sir YK Pao Ctr. for Cancer, State Key Lab of Translational Oncology, Dept of Clinical Oncology, Cancer Epigenetics Laboratory

Yichao Fan

The Chinese University of Hong Kong, Li Ka Shing Inst. of Health Sciences, Sir YK Pao Ctr. for Cancer, State Key Lab of Translational Oncology, Dept of Clinical Oncology, Cancer Epigenetics Laboratory

Xin Huang

The Chinese University of Hong Kong, Li Ka Shing Inst. of Health Sciences, Sir YK Pao Ctr. for Cancer, State Key Lab of Translational Oncology, Dept of Clinical Oncology, Cancer Epigenetics Laboratory

Lan Zhong

The Chinese University of Hong Kong, Li Ka Shing Inst. of Health Sciences, Sir YK Pao Ctr. for Cancer, State Key Lab of Translational Oncology, Dept of Clinical Oncology, Cancer Epigenetics Laboratory

Xing-sheng Shu

The Chinese University of Hong Kong, Li Ka Shing Inst. of Health Sciences, Sir YK Pao Ctr. for Cancer, State Key Lab of Translational Oncology, Dept of Clinical Oncology, Cancer Epigenetics Laboratory; Shenzhen University - School of Medicine; Shenzhen University - Institute of Molecular Medicine

Jie Luo

The Chinese University of Hong Kong, Li Ka Shing Inst. of Health Sciences, Sir YK Pao Ctr. for Cancer, State Key Lab of Translational Oncology, Dept of Clinical Oncology, Cancer Epigenetics Laboratory

Li Lu

The Chinese University of Hong Kong, Li Ka Shing Inst. of Health Sciences, Sir YK Pao Ctr. for Cancer, State Key Lab of Translational Oncology, Dept of Clinical Oncology, Cancer Epigenetics Laboratory

Tingxiu Xiang

Chongqing Medical University, First Affiliated Hospital, Chongqing Key Laboratory of Molecular Oncology and Epigenetics

Anthony TC Chan

The Chinese University of Hong Kong, Li Ka Shing Inst. of Health Sciences, Sir YK Pao Ctr. for Cancer, State Key Lab of Translational Oncology, Dept of Clinical Oncology, Cancer Epigenetics Laboratory

Winnie Yeo

The Chinese University of Hong Kong, Li Ka Shing Inst. of Health Sciences, Sir YK Pao Ctr. for Cancer, State Key Lab of Translational Oncology, Dept of Clinical Oncology, Cancer Epigenetics Laboratory

Ceshi Chen

Chinese Academy of Sciences (CAS), Kunming Institute of Zoology, Key Laboratory of Animal Models and Human Disease Mechanisms

Wai Yee Chan

The Chinese University of Hong Kong (CUHK) - School of Biomedical Sciences

Richard L. Huganir

Johns Hopkins University, School of Medicine, Department of Neuroscience

Qian Tao

The Chinese University of Hong Kong, Li Ka Shing Inst. of Health Sciences, Sir YK Pao Ctr. for Cancer, State Key Lab of Translational Oncology, Dept of Clinical Oncology, Cancer Epigenetics Laboratory

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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

Suggested Citation

Li, Lili and Fan, Yichao and Huang, Xin and Zhong, Lan and Shu, Xing-sheng and Luo, Jie and Lu, Li and Xiang, Tingxiu and Chan, Anthony TC and Yeo, Winnie and Chen, Ceshi and Chan, Wai Yee and Huganir, Richard L. and Tao, Qian, Novel Tumor Suppressive Role of the RAS GTPase-Activating Protein RASA5 to RAS Signaling Perturbation in Human Carcinomas (March 22, 2019). Available at SSRN: https://ssrn.com/abstract=3357918 or http://dx.doi.org/10.2139/ssrn.3357918
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Lili Li

The Chinese University of Hong Kong, Li Ka Shing Inst. of Health Sciences, Sir YK Pao Ctr. for Cancer, State Key Lab of Translational Oncology, Dept of Clinical Oncology, Cancer Epigenetics Laboratory

Hong Kong
Hong Kong

Yichao Fan

The Chinese University of Hong Kong, Li Ka Shing Inst. of Health Sciences, Sir YK Pao Ctr. for Cancer, State Key Lab of Translational Oncology, Dept of Clinical Oncology, Cancer Epigenetics Laboratory

Hong Kong
Hong Kong

Xin Huang

The Chinese University of Hong Kong, Li Ka Shing Inst. of Health Sciences, Sir YK Pao Ctr. for Cancer, State Key Lab of Translational Oncology, Dept of Clinical Oncology, Cancer Epigenetics Laboratory

Hong Kong
Hong Kong

Lan Zhong

The Chinese University of Hong Kong, Li Ka Shing Inst. of Health Sciences, Sir YK Pao Ctr. for Cancer, State Key Lab of Translational Oncology, Dept of Clinical Oncology, Cancer Epigenetics Laboratory ( email )

Hong Kong
Hong Kong

Xing-sheng Shu

The Chinese University of Hong Kong, Li Ka Shing Inst. of Health Sciences, Sir YK Pao Ctr. for Cancer, State Key Lab of Translational Oncology, Dept of Clinical Oncology, Cancer Epigenetics Laboratory

Hong Kong
Hong Kong

Shenzhen University - School of Medicine

China

Shenzhen University - Institute of Molecular Medicine

China

Jie Luo

The Chinese University of Hong Kong, Li Ka Shing Inst. of Health Sciences, Sir YK Pao Ctr. for Cancer, State Key Lab of Translational Oncology, Dept of Clinical Oncology, Cancer Epigenetics Laboratory

Hong Kong
Hong Kong

Li Lu

The Chinese University of Hong Kong, Li Ka Shing Inst. of Health Sciences, Sir YK Pao Ctr. for Cancer, State Key Lab of Translational Oncology, Dept of Clinical Oncology, Cancer Epigenetics Laboratory

Hong Kong
Hong Kong

Tingxiu Xiang

Chongqing Medical University, First Affiliated Hospital, Chongqing Key Laboratory of Molecular Oncology and Epigenetics

China

Anthony TC Chan

The Chinese University of Hong Kong, Li Ka Shing Inst. of Health Sciences, Sir YK Pao Ctr. for Cancer, State Key Lab of Translational Oncology, Dept of Clinical Oncology, Cancer Epigenetics Laboratory

Hong Kong
Hong Kong

Winnie Yeo

The Chinese University of Hong Kong, Li Ka Shing Inst. of Health Sciences, Sir YK Pao Ctr. for Cancer, State Key Lab of Translational Oncology, Dept of Clinical Oncology, Cancer Epigenetics Laboratory

Hong Kong
Hong Kong

Ceshi Chen

Chinese Academy of Sciences (CAS), Kunming Institute of Zoology, Key Laboratory of Animal Models and Human Disease Mechanisms

No.32 Jiaochang Donglu
Kunming, Yunnan 650223
China

Wai Yee Chan

The Chinese University of Hong Kong (CUHK) - School of Biomedical Sciences

China

Richard L. Huganir

Johns Hopkins University, School of Medicine, Department of Neuroscience

Baltimore, MD 21218
United States

Qian Tao (Contact Author)

The Chinese University of Hong Kong, Li Ka Shing Inst. of Health Sciences, Sir YK Pao Ctr. for Cancer, State Key Lab of Translational Oncology, Dept of Clinical Oncology, Cancer Epigenetics Laboratory

Hong Kong
Hong Kong

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