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 Cheng^1,† , Fanying Li^2,† , Maolei Zhang^2,† , 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 Yao^3,* , Jianbo Xu^7,* , Chao Yan^1,8,9,10,* , Nu Zhang^2,5,11,*

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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