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

2015; Springer Nature; Volume: 35; Issue: 27 Linguagem: Inglês

10.1038/onc.2015.408

1476-5594

Isabel Adrados, Javier Larrasa-Alonso, Antonio Galarreta, Irene López‐Antona, Camino Menéndez, María Abad, Jesús Gil, Gema Moreno‐Bueno, Ignacio Palmero,

Genomics and Chromatin Dynamics

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.