SRP19 and the protein secretion machinery is a targetable vulnerability in cancers with APC loss

• 成果类型: Article
• 署名作者: Xi, Xinqi; Liu, Ling; Tuano, Natasha; Tailhades, Julien; Mouradov, Dmitri; Steen, Jason; Sieber, Oliver; Cryle, Max; Nguyen-Dumont, Tu; Segelov, Eva; Rosenbluh, Joseph
• 署名单位: Monash University; Monash University; Murdoch Children's Research Institute; Walter & Eliza Hall Institute; University of Melbourne; Monash University; University of Melbourne; University of Melbourne; University of Bern; University Hospital of Bern; University of Geneva; University of Bern; University Hospital of Bern; Monash University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11745
• DOI: 10.1073/pnas.2409677122
• 发表日期: 2025-04-10
• 关键词: mutations; gene; rna; insights; reveals; cells

摘要

Loss of the tumor suppressor gene (TSG) Adenomatous Polyposis Coli (APC) is a hallmark event in colorectal cancers. Since it is not possible to directly target a TSG, no treatment options are available for these patients. Here, we identify SRPJ9 and the protein secretion machinery as a unique vulnerability in cancers with heterozygous APC loss. SRPJ9 is located 15 kb from APC and is almost always codeleted in these tumors. Heterozygous APC/SRPJ9 loss leads to lower levels of SRPJ9 mRNA and protein. Consequently, cells with APC/SRPJ9loss are vulnerable to partial suppression of SRPJ9. Moreover, we show that SRPJ9 is rate limiting for the formation of the Signal Recognition Particle, a complex that mediates ER-protein translocation, and thus, heterozygous SRPJ9 loss leads to less protein secretion and higher levels of ER-stress. As a result, low-dose arsenic trioxide induces ER-stress and inhibits proliferation in cultured cell lines and animal models. Our work identifies a strategy to treat cancers with APC deletion and provides a framework for identifying and translating vulnerabilities associated with loss of a TSG.