1. Academic Validation
  2. A novel protein RASON encoded by a lncRNA controls oncogenic RAS signaling in KRAS mutant cancers

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

  • Cell Res. 2022 Oct 14. doi: 10.1038/s41422-022-00726-7.
Rongjie Cheng # 1 Fanying Li # 2 Maolei Zhang # 2 Xin Xia 2 Jianzhuang Wu 1 Xinya Gao 2 Huangkai Zhou 2 Zhi Zhang 3 Nunu Huang 2 Xuesong Yang 2 Yaliang Zhang 1 Shunli Shen 4 Tiebang Kang 5 Zexian Liu 5 Feizhe Xiao 6 Hongwei Yao 7 Jianbo Xu 8 Chao Yan 9 10 11 12 Nu Zhang 13 14 15
Affiliations

Affiliations

  • 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 Institute of Molecular Enzymology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, Jiangsu, China. [email protected]
  • 8 Department of Gastrointestinal surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. [email protected]
  • 9 State Key Laboratory of Pharmaceutical Biotechnology, School of life Sciences, Nanjing University, Nanjing, Jiangsu, China. [email protected]
  • 10 Chemistry and Biomedicine Innovation Center, Institute of Artificial Intelligence Biomedicine, Nanjing University, Nanjing, Jiangsu, China. [email protected]
  • 11 Engineering Research Center of Protein and Peptide Medicine, Ministry of Education, Nanjing, Jiangsu, China. [email protected]
  • 12 Institute of Pancreatology, Nanjing University, Nanjing, China. [email protected]
  • 13 Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. [email protected]
  • 14 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China. [email protected]
  • 15 Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, Guangdong, China. [email protected]
  • # Contributed equally.
Abstract

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.

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