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Volume 33, No 1, Jan 2023

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 33 Issue 1, January 2023: 30-45

ORIGINAL ARTICLES

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

Rongjie Cheng1,† , Fanying Li2,† , Maolei Zhang2,† , Xin Xia2 , Jianzhuang Wu1 , Xinya Gao2 , Huangkai Zhou2 , Zhi Zhang3 , Nunu Huang2 , Xuesong Yang2 , Yaliang Zhang1 , Shunli Shen4 , Tiebang Kang5 , Zexian Liu5 , Feizhe Xiao6 , Hongwei Yao3,* , Jianbo Xu7,* , Chao Yan1,8,9,10,* , Nu Zhang2,5,11,*

1State Key Laboratory of Pharmaceutical Biotechnology, School of life Sciences, Nanjing University, Nanjing, Jiangsu, China
2Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
3Institute of Molecular Enzymology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, Jiangsu, China
4Department of Hepatological surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
5State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
6Department of Scientific Research Section, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
7Department of Gastrointestinal surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
8Chemistry and Biomedicine Innovation Center, Institute of Artificial Intelligence Biomedicine, Nanjing University, Nanjing, Jiangsu, China
9Engineering Research Center of Protein and Peptide Medicine, Ministry of Education, Nanjing, Jiangsu, China
10Institute of Pancreatology, Nanjing University, Nanjing, China
11Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, Guangdong, China
These authors contributed equally: Rongjie Cheng, Fanying Li, Maolei Zhang
Correspondence: Hongwei Yao(hwyao@suda.edu.cn)Jianbo Xu(xjianb@mail.sysu.edu.cn)Chao Yan(yanchao@nju.edu.cn)Nu Zhang(zhangnu2@mail.sysu.edu.cn)

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 KRASG12C 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-KrasG12D; Trp53R172H/+ mice. Mechanistically, RASON directly binds to KRASG12D/V and inhibits both intrinsic and GTPase activating protein (GAP)-mediated GTP hydrolysis, thus sustaining KRASG12D/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.


https://doi.org/10.1038/s41422-022-00726-7

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