A novel protein RASON encoded by a lncRNA controls oncogenic RAS signaling in KRAS mutant cancers  

作　　者：Rongjie Cheng Fanying Li Maolei Zhang Xin Xia Jianzhuang Wu Xinya Gao Huangkai Zhou Zhi Zhang Nunu Huang Xuesong Yang Yaliang Zhang Shunli Shen Tiebang Kang Zexian Liu Feizhe Xiao Hongwei Yao Jianbo Xu Chao Yan Nu Zhang 

机构地区：[1]State Key Laboratory of Pharmaceutical Biotechnology,School of life Sciences,Nanjing University,Nanjing,Jiangsu,China [2]Department of Neurosurgery,The First Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong,China [3]Institute of Molecular Enzymology,School of Biology and Basic Medical Sciences,Soochow University,Suzhou,Jiangsu,China [4]Department of Hepatological surgery,The First Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong,China [5]State Key Laboratory of Oncology in South China,Collaborative Innovation Center for Cancer Medicine,Sun Yat-sen University Cancer Center,Guangzhou,Guangdong,China [6]Department of Scientific Research Section,The First Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong,China [7]Department of Gastrointestinal surgery,The First Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong,China [8]Chemistry and Biomedicine Innovation Center,Institute of Artificial Intelligence Biomedicine,Nanjing University,Nanjing,Jiangsu,China [9]Engineering Research Center of Protein and Peptide Medicine,Ministry of Education,Nanjing,Jiangsu,China [10]Institute of Pancreatology,Nanjing University,Nanjing,China [11]Guangdong Provincial Key Laboratory of Brain Function and Disease,Guangzhou,Guangdong,China

出　　处：《Cell Research》2023年第1期30-45,共16页细胞研究（英文版）

基　　金：This work was jointly supported by the National Natural Science Distinguished Youth Foundation of China(82125024 to N.Z.);the National Natural Science Outstanding Youth Foundation of China(81822033 to N.Z.);the National Key R&D Program of China(2016YFA0503000 to N.Z.and 2020YFA0713800 to C.Y.);the National Natural Science Foundation of China(81772683 to N.Z.,21877060 to C.Y.,81871915 to J.X.,and 31870735 to H.Y.).

摘　　要：Mutations of the RAS oncogene are found in around 30%of all human cancers yet direct targeting of RAS is still considered clinically impractical except for the KRAS^(G12C)mutant.Here we report that RAS-ON(RASON),a novel protein encoded by the long intergenic non-protein coding RNA 00673(LINC00673),is a positive regulator of oncogenic RAS signaling.RASON is aberrantly overexpressed in pancreatic ductal adenocarcinoma(PDAC)patients,and it promotes proliferation of human PDAC cell lines in vitro and tumor growth in vivo.CRISPR/Cas9-mediated knockout of Rason in mouse embryonic fibroblasts inhibits KRAS-mediated tumor transformation.Genetic deletion of Rason abolishes oncogenic KRAS-driven pancreatic and lung cancer tumorigenesis in LSL Kras^(G12D);Trp53R172H/+mice.Mechanistically,RASON directly binds to KRAS^(G12D)/V and inhibits both intrinsic and GTPase activating protein(GAP)-mediated GTP hydrolysis,thus sustaining KRAS^(G12D/V)in the GTP-bound hyperactive state.Therapeutically,deprivation of RASON sensitizes KRAS mutant pancreatic cancer cells and patient-derived organoids to EGFR inhibitors.Our findings identify RASON as a critical regulator of oncogenic KRAS signaling and a promising therapeutic target for KRAS mutant cancers.

关 键 词：KRAS CRISPR/Cas9 CANCERS 

分 类 号：R73[医药卫生—肿瘤]