PTBP1-Mediated Alternative Splicing Regulates the Inflammatory Secretome and the Pro-tumorigenic Effects of Senescent Cells

Oncogene-induced senescence is a potent tumor-suppressive response. Paradoxically, senescence also induces an inflammatory secretome that promotes carcinogenesis and age-related pathologies. Consequently, the senescence-associated secretory phenotype (SASP) is a potential therapeutic target. Here, w...

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Detalles Bibliográficos
Autores: Georgilis, Athena, Klotz, Sabrina, Hanley, Christopher J., Herranz, Nicolas, Weirich, Benedikt, Morancho, Beatriz|||0000-0003-3369-8647, Leote, Ana Carolina, D'Artista, Luana, Gallage, Suchira, Seehawer, Marco, Carroll, Thomas, Dharmalingam, Gopuraja, Wee, Keng Boon, Mellone, Marco, Pombo, Joaquim, Heide, Danijela, Guccione, Ernesto, Arribas, Joaquín V|||0000-0002-0504-0664, Barbosa-Morais, Nuno L., Heikenwälder, Mathias, Thomas, Gareth J., Zender, Lars, Gil, Jesús
Tipo de recurso: artículo
Fecha de publicación:2018
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:227946
Acceso en línea:https://ddd.uab.cat/record/227946
https://dx.doi.org/urn:doi:10.1016/j.ccell.2018.06.007
Access Level:acceso abierto
Palabra clave:SASP
Senescence
RNAi screen
Alternative splicing
PTBP1
EXOC7
Oncogene-induced senescence
Descripción
Sumario:Oncogene-induced senescence is a potent tumor-suppressive response. Paradoxically, senescence also induces an inflammatory secretome that promotes carcinogenesis and age-related pathologies. Consequently, the senescence-associated secretory phenotype (SASP) is a potential therapeutic target. Here, we describe an RNAi screen for SASP regulators. We identified 50 druggable targets whose knockdown suppresses the inflammatory secretome and differentially affects other SASP components. Among the screen candidates was PTBP1. PTBP1 regulates the alternative splicing of genes involved in intracellular trafficking, such as EXOC7, to control the SASP. Inhibition of PTBP1 prevents the pro-tumorigenic effects of the SASP and impairs immune surveillance without increasing the risk of tumorigenesis. In conclusion, our study identifies SASP inhibition as a powerful and safe therapy against inflammation-driven cancer. By performing a genetic screen for regulators of the senescence-associated secretory phenotype (SASP), Georgilis et al. identify PTBP1, which controls SASP by regulating alternative splicing of genes involved in intracellular trafficking such as EXOC7. PTBP1 knockdown blocks the tumor-promoting functions of SASP.

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