SIRT7 promotes lung cancer progression by destabilizing the tumor suppressor ARF

• 成果类型: Article
• 署名作者: Kumari, Poonam; Tarighi, Shahriar; Fuchshuber, Eva; Li, Luhan; Fernandez-Duran, Irene; Wang, Meilin; Ayoson, Joshua; Castello-Garcia, Jose Manuel; Gamez-Garcia, Andres; Espinosa-Alcantud, Maria; Sreenivasan, Krishnamoorthy; Guenther, Stefan; Olivella, Mireia; Savai, Rajkumar; Yue, Shijing; Vaquero, Alejandro; Braun, Thomas; Ianni, Alessandro
• 署名单位: Max Planck Society; Nankai University; Institut de Recerca Contra la Leucemia Josep Carreras (IJC); Max Planck Society; Universitat de Vic - Universitat Central de Catalunya (UVic-UCC); Justus Liebig University Giessen
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12587
• DOI: 10.1073/pnas.2409269121
• 发表日期: 2024-06-18
• 关键词: ink4a locus; protein; p53; nucleophosmin; expression; p14(arf)

摘要

Sirtuin 7 (SIRT7) is a member of the mammalian family of nicotinamide adenine dinucleotide (NAD + ) - dependent histone/protein deacetylases, known as sirtuins. It acts as a potent oncogene in numerous malignancies, but the molecular mechanisms employed by SIRT7 to sustain lung cancer progression remain largely uncharacterized. We demonstrate that SIRT7 exerts oncogenic functions in lung cancer cells by destabilizing the tumor suppressor alternative reading frame (ARF). SIRT7 directly interacts with ARF and prevents binding of ARF to nucleophosmin, thereby promoting proteasomaldependent degradation of ARF. We show that SIRT7 - mediated degradation of ARF increases expression of protumorigenic genes and stimulates proliferation of non - small - cell lung cancer (NSCLC) cells both in vitro and in vivo in a mouse xenograft model. Bioinformatics analysis of transcriptome data from human lung adenocarcinomas revealed a correlation between SIRT7 expression and increased activity of genes normally repressed by ARF. We propose that disruption of SIRT7-ARF signaling stabilizes ARF and thus attenuates cancer cell proliferation, offering a strategy to mitigate NSCLC progression.