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

AuthorsAdrados, Isabel; Larrasa-Alonso, Javier; Galarreta, A.; López-Antona, Irene; Menéndez, Carlos; Menéndez, Camino ; Abad, María; Moreno-Bueno, Gema ; Palmero, Ignacio
Issue Date2016
PublisherNature Publishing Group
CitationOncogene 35(27): 3485-3494 (2016)
AbstractCellular 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.
Identifiersdoi: 10.1038/onc.2015.408
e-issn: 1476-5594
issn: 0950-9232
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