The homeoprotein SIX1 controls cellular senescence through the regulation of p16INK4A and differentiation-related genes.
Cellular senescence is an antiproliferative response with essential functions in tumor suppression and tissue homeostasis. Here we show that SIX1, a member of the SIX family of homeobox transcriptional factors, is a novel repressor of senescence. Our data show that SIX1 is specifically downregulated in fibroblasts upon oncogenic stress and other pro-senescence stimuli, as well as in senescent skin premalignant lesions. Silencing of SIX1 in human fibroblasts suffices to trigger senescence, which is mediated by p16INK4A and lacks a canonical senescence-associated secretory phenotype. Interestingly, SIX1-associated senescence is further characterized by the expression of a set of development and differentiation-related genes that significantly overlap with genes associated with SIX1 in organogenesis or human tumors, and show coincident regulation in oncogene-induced senescence. Mechanistically, we show that gene regulation by SIX1 during senescence is mediated, at least in part, by cooperation with Polycomb repressive complexes. In summary, our results identify SIX1, a key development regulator altered in human tumors, as a critical repressor of cellular senescence, providing a novel connection between senescence, differentiation and tumorigenesis.
Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid, Spain.
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Adrados
Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid, Spain.
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J
Larrasa-Alonso
Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid, Spain.
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Galarreta
Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid, Spain.
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López-Antona
Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid, Spain.
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Menéndez
Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid, Spain.
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Abad
Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London, UK.
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0000-0002-4303-6260
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Gil
Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid, Spain.|Departamento de Bioquímica, UAM, IdiPAZ (Instituto de Investigación Sanitaria La Paz) and Fundación MD Anderson Internacional, Madrid, Spain.
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Moreno-Bueno
Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid, Spain.
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Palmero
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D057507:Mice, 129 Strain; D010212:Papilloma / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D018398:Homeodomain Proteins; C099236:SIX1 protein, human