SIRT7 promotes lung cancer progression by destabilizing the tumor suppressor ARF

Author:

Kumari Poonam1ORCID,Tarighi Shahriar1ORCID,Fuchshuber Eva1,Li Luhan2,Fernández-Duran Irene3,Wang Meilin2,Ayoson Joshua4,Castelló-García Jose Manuel3,Gámez-García Andrés3,Espinosa-Alcantud Maria3,Sreenivasan Krishnamoorthy1,Guenther Stefan1,Olivella Mireia56,Savai Rajkumar47ORCID,Yue Shijing2ORCID,Vaquero Alejandro3ORCID,Braun Thomas1ORCID,Ianni Alessandro13ORCID

Affiliation:

1. Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim 61231, Germany

2. School of Medicine, Nankai University, Tianjin 300071, China

3. Chromatin Biology Laboratory, Josep Carreras Leukaemia Research Institute, Badalona, Barcelona, Catalonia 08916, Spain

4. Department of Lung Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim 61231, Germany

5. Facultat de Ciències, Tecnologia I Enginyeries, Universitat de Vic-Universitat Central de Catalunya, Vic, Barcelona 08500, Spain

6. Institut de Recerca i Innovació en Ciències de la Vida i de la Salut a la Catalunya Central, Vic, Barcelona 08500, Spain

7. Lung Microenvironmental Niche in Cancerogenesis, Institute for Lung Health, Justus Liebig University, Giessen D-35392, Germany

Abstract

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 proteasomal-dependent 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.

Funder

Deutsche Forschungsgemeinschaft

EC | Horizon Europe | Excellent Science | HORIZON EUROPE Marie Sklodowska-Curie Actions

Publisher

Proceedings of the National Academy of Sciences

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