Our results further indicate that low expression

Our results further indicate that low expression of p300/CBP in CRC is directly associated with poor clinical therapeutic outcome of 5-FU treatment, potentially providing a new set of biomarkers to predict chemo-sensitivity. Although the ability of low expression of p300/CBP to predict poor prognosis in CRC has been reported [31], [45], [46], the underlying mechanisms for this association remain unclear. For example, Huh investigated the expression of p300 in 199 CRC patients who underwent radical surgery and 5-FU-based chemotherapy, and found that long-term survival rate was significantly lower in p300 low expression patients than in p300 high expression patients [31]. Since over 70% of CRC patients undergo 5-FU based chemotherapy, it is possible that the unfavorable prognosis of those CRC patients with low expression of p300/CBP may be associated with a poor response of this population to 5-FU treatment. Our work suggests that the immunohistochemical evaluation of p300/CBP in CRC samples may be helpful in identifying who will benefit from 5-FU-based chemotherapy, and underscores the potential of p300/CBP to be clinical biomarkers to predict the therapeutic outcome of 5-FU treatment.
Funding This work was supported by National Natural Science Foundation of China grants NSFC91319302; Beijing Municipal Administration of Hospitals' Youth ProgramQML20161105; Discipline Construction Funding of Shenzhen (2016) and Shenzhen Municipal Commission of Science and Technology Innovation grants JCYJ20160427104855100.
Author contributions
Acknowledgements
Introduction Cellular senescence is a state of durable pde-5 inhibitors arrest induced by stressors such as DNA damage, telomere erosion, and oncogene activation (He and Sharpless, 2017). Senescent cells express high levels of β-galactosidase (SA-β-gal), p16, hypo-phosphorylated Rb, inflammatory cytokines (known as the senescence-associated secretory phenotype or SASP), and chromatin changes (Coppé et al., 2010). The latter include senescence-associated heterochromatic foci (SAHF) (Narita et al., 2003), inappropriate euchromatin (Shah et al., 2013), and chromatin fragmentation with cytoplasmic extrusion (Dou et al., 2015, Dou et al., 2017, Ivanov et al., 2013). The anti-proliferative property and acute SASP of senescent cells serves a tumor suppressive function, however, chronic SASP contributes to inflammation, tissue aging, and disease (Coppé et al., 2010). Recent evidence points to the causal roles of senescent cells in decreasing healthspan and lifespan. For example, (1) aging human tissues show accumulation of senescent cells (van Deursen, 2014), (2) cells isolated from human patients suffering from premature aging syndromes show premature senescence in culture (Aliper et al., 2015), (3) targeted elimination of senescent cells extends healthspan and lifespan in mice (Baker et al., 2011, Baker et al., 2016), (4) “senolytic” compounds that induce senescent cell death show lifespan extension and therapeutic benefits in several age-associated diseases (Kirkland and Tchkonia, 2017), and (5) SASP mediates inflammation and cancer (Coppé et al., 2010). Senescent cells accumulate in aged tissues in part due to replicative exhaustion and/or chronic telomere shortening in cells capable of division (Hornsby, 2002). This phenomenon, called replicative senescence (RS), can be recapitulated in vitro by repeated passage of cells in culture (Campisi, 1997). RS cells show profound chromatin reorganization with changes in both DNA and histone modifications (Sen et al., 2016). For example, RS cells show a general loss of all canonical histones (O’Sullivan et al., 2010), upregulation of an alternative pool of histones and histone variants (including H3.3) (Rai et al., 2014), downregulation of lamin B1, and/or loss of nuclear-lamina-associated heterochromatin (Dou et al., 2015, Shah et al., 2013). Concomitantly, a new chromatin landscape is formed that exerts a strong anti-proliferative, pro-senescence cellular phenotype. Our previous studies revealed broad areas of enrichment (mesas) in trimethylated lysine 4 on histone H3 (H3K4me3) and H3K27me3 over lamin B1-associated domains and depletion (canyons) of H3K27me3 in putative enhancers (Shah et al., 2013). Repressive H4K20me3 is increased in SAHFs and repeat elements (Nelson et al., 2016). These changes indicate a general reorganization of chromatin domains outside coding regions and predict consequential changes in gene expression.