The ubiquitin code of RAS proteins: Decoding its role in cancer progression
Yedan Shi,
Yong Shen,
Xiuyuan Zhang,
Ning Zhu,
Yuwei Ding,
Ying Yuan,
Juan Wang
Affiliations
Yedan Shi
Department of Medical Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; Zhejiang Provincial Clinical Research Center for CANCER, Hangzhou, Zhejiang 310009, China; Cancer Center of Zhejiang University, Hangzhou, Zhejiang 310009, China
Yong Shen
Department of Medical Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; Zhejiang Provincial Clinical Research Center for CANCER, Hangzhou, Zhejiang 310009, China; Department of Breast Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
Xiuyuan Zhang
Department of Medical Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; Zhejiang Provincial Clinical Research Center for CANCER, Hangzhou, Zhejiang 310009, China; Cancer Center of Zhejiang University, Hangzhou, Zhejiang 310009, China
Ning Zhu
Department of Medical Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; Zhejiang Provincial Clinical Research Center for CANCER, Hangzhou, Zhejiang 310009, China; Cancer Center of Zhejiang University, Hangzhou, Zhejiang 310009, China
Yuwei Ding
Department of Medical Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; Zhejiang Provincial Clinical Research Center for CANCER, Hangzhou, Zhejiang 310009, China; Cancer Center of Zhejiang University, Hangzhou, Zhejiang 310009, China
Ying Yuan
Department of Medical Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; Zhejiang Provincial Clinical Research Center for CANCER, Hangzhou, Zhejiang 310009, China; Cancer Center of Zhejiang University, Hangzhou, Zhejiang 310009, China; Correspondence
Juan Wang
Department of Medical Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; Zhejiang Provincial Clinical Research Center for CANCER, Hangzhou, Zhejiang 310009, China; Cancer Center of Zhejiang University, Hangzhou, Zhejiang 310009, China; Correspondence
Summary: RAS proteins, as the most frequently mutated oncoproteins in human cancers, drive tumor proliferation, metastasis, and therapeutic resistance. Recent studies have revealed that ubiquitination dynamically regulates the stability, membrane localization, and signaling transduction of RAS proteins, profoundly impacting their oncogenic functions. A series of ubiquitination sites, E3 ligases, deubiquitinases, and regulatory proteins are involved in RAS ubiquitination. We also analyze the heterogeneity of ubiquitination patterns across distinct RAS isoforms (KRAS4A, KRAS4B, NRAS, and HRAS) and their functional disparities in cancers. Targeting the ubiquitination pathway offers novel strategies to overcome RAS proteins. Future research should integrate protein structure analysis and high-throughput screening to develop specific ubiquitination modulators and explore combination RAS ubiquitination targeting strategies with RAS inhibitors or immunotherapy, aiming to overcome RAS-driven malignant phenotypes.
