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The homeoprotein SIX1 controls cellular senescence through the regulation of p16INK4A and differentiation-related genes

Oncogene volume 35, pages 3485–3494 (2016)Cite this article

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Abstract

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.

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Acknowledgements

We thank Manuel Serrano, Daniel Peeper and René Bernards for cells and reagents, and Masashi Narita for reagents and sharing unpublished data. This work was supported by grants from the Spanish Government (SAF2012-32117) to IP, Instituto de Salud Carlos III (PI13/00132 and RETIC-RD12/0036/0007) and Regional Government of Madrid (S2010/BMD-2303) to GM-B. IA is the recipient of a fellowship from the Spanish Government FPI program.

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Author notes

  1. I Adrados

    Present address: 4Present Address: The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.,

  2. J Larrasa-Alonso

    Present address: 5Present Address: Centro Nacional de Investigaciones Cardiovasculares, CNIC, Madrid 28029, Spain.,

  3. C Menéndez & M Abad

    Present address: 6Present Address: Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain.,

Authors and Affiliations

  1. Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, Madrid, Spain

    I Adrados, J Larrasa-Alonso, A Galarreta, I López-Antona, C Menéndez, M Abad, G Moreno-Bueno & I Palmero

  2. Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London, UK

    J Gil

  3. Departamento de Bioquímica, UAM, IdiPAZ (Instituto de Investigación Sanitaria La Paz) and Fundación MD Anderson Internacional, Madrid, Spain

    G Moreno-Bueno

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Adrados, I., Larrasa-Alonso, J., Galarreta, A. et al. The homeoprotein SIX1 controls cellular senescence through the regulation of p16INK4A and differentiation-related genes. Oncogene 35, 3485–3494 (2016). https://doi.org/10.1038/onc.2015.408

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