FOXA1 mediates p16INK4a activation during cellular senescence

Abstract

Mechanisms governing the transcription of p16INK4a , one of the master regulators of cellular senescence, have been extensively studied. However, little is known about chromatin dynamics taking place at its promoter and distal enhancer. Here, we report that Forkhead box A1 protein (FOXA1) is significantly upregulated in both replicative and oncogene-induced senescence, and in turn activates transcription of p16INK4a through multiple mechanisms. In addition to acting as a classic sequence-specific transcriptional activator, FOXA1 binding leads to a decrease in nucleosome density at the p16INK4a promoter in senescent fibroblasts. Moreover, FOXA1, itself a direct target of Polycomb-mediated repression, antagonizes Polycomb function at the p16 INK4a locus. Finally, a systematic survey of putative FOXA1 binding sites in the p16INK4a genomic region revealed an B150 kb distal element that could loop back to the promoter and potentiate p16INK4a expression. Overall, our findings establish several mechanisms by which FOXA1 controls p16 INK4a expression during cellular senescence.

3′ UTR lengthening as a novel mechanism in regulating cellular senescence

“…After extensive proliferation, senescence occurs because of telomere shortening and loss in the absence of endogenous telomerase activity (Hayflick and Moorhead 1961;Olovnikov 1996). In addition to telomere erosion, many stimuli and stresses can cause cellular senescence, including DNA double-strand breaks, strong mitogenic signals, oxidative stress, and ectopic expression of cyclin-dependent kinase inhibitors (CDKIs) (Xue et al 2004;Rodier and Campisi 2011;Li et al 2013). Numerous morphological and molecular markers of senescent cells have been identified in recent decades, which include a flattened and enlarged cell morphology, increased senescence-associated β-galactosidase (SA-β-gal) activity, reduced proliferation rate, and expression of tumor suppressors, cell cycle inhibitors, and DNA damage markers (Dimri et al 1995;Busuttil et al 2003;Lopez-Otin et al 2013;Munoz-Espin and Serrano 2014).…”

Forkhead-box A1 induces cell senescence in endometrial cancer by regulating p16INK4a

“…Our data support the hypothesis that FOXA1 is a transcription factor that is induced during senescence in EC. Li et al showed that FOXA1 was significantly upregulated in senescent human 2BS diploid fibroblast cells (10); therefore, we proposed that FOXA1 is also associated with senescence in EC, the functional role of FOXA1 in tumor progression should not be restricted to its ̔pioneering̓ role associated with hormone receptors.…”

“…INK4a promoter, which is the key senescence-associated gene (10,20). To understand the interplay of chromatin, senescence and EC, further studies are required to elucidate the functional and causal roles of senescence-associated chromatin features in preventing tumor phenotype and to delineate the underlying mechanisms.…”

“…It has been reported that in senescence, FOXA1 binds to the promoter region of p16, stimulates chromatin remodeling and enables long-range promoter-enhancer communication to promote p16 expression (10).…”

FOXA1 antagonizes EZH2-mediated CDKN2A repression in carcinogenesis

“…Our functional investigations on transcription factors (TFs) with a potential to activate CDKN2A in cellular senescence revealed that FOXA1 is a key TF for CDKN2A expression [6]. FOXA1 is a member of forkhead family TFs with remarkable pioneering activity to open closed chromatin for its subsequent cooperation with other master TF in embryogenesis and organ development [7,8].…”