Histone Modifications in Senescence-Associated Resistance to Apoptosis by Oxidative Stress

Abstract

Aging and age-related diseases are associated with cellular senescence that results in variable apoptosis susceptibility to oxidative stress. Although fibroblast senescence has been associated with apoptosis resistance, mechanisms for this have not been well defined. In this report, we studied epigenetic mechanisms involving histone modifications that confer apoptosis resistance to senescent human diploid fibroblasts (HDFs). HDFs that undergo replicative senescence display typical morphological features, express senescence-associated β-galactosidase, and increased levels of the tumor suppressor genes, p16, p21, and caveolin-1. Senescent HDFs are more resistant to oxidative stress (exogenous H2O2)-induced apoptosis in comparison to non-senescent (control) HDFs; this is associated with constitutively high levels of the anti-apoptotic gene, Bcl-2, and low expression of the pro-apoptotic gene, Bax. Cellular senescence is characterized by global increases in H4K20 trimethylation and decreases in H4K16 acetylation in association with increased activity of Suv420h2 histone methyltransferase (which targets H4K20), decreased activity of the histone acetyltransferase, Mof (which targets H4K16), as well as decreased total histone acetyltransferase activity. In contrast to Bax gene, chromatin immunoprecipitation studies demonstrate marked enrichment of the Bcl-2 gene with H4K16Ac, and depletion with H4K20Me3, predicting active transcription of this gene in senescent HDFs. These data indicate that both global and locus-specific histone modifications of chromatin regulate altered Bcl-2:Bax gene expression in senescent fibroblasts, contributing to its apoptosis-resistant phenotype.

Mdm2 and Aurora Kinase A Inhibitors Synergize to Block Melanoma Growth by Driving Apoptosis and Immune Clearance of Tumor Cells

“…Senescent cells can acquire resistance to certain pro-apoptotic stimuli, including serum withdrawal, radiation, oxidative stress and treatment with DNA damaging drugs (27–30). Notably, the senescence-associated resistance to apoptosis has been linked to impaired activation of p53 (29,31).…”

The NSL Chromatin-Modifying Complex Subunit KANSL2 Regulates Cancer Stem–like Properties in Glioblastoma That Contribute to Tumorigenesis

“…For Immunohistochemistry staining with Leica Bond Max automated Stainer, the following antibodies were used: anti-KANSL2 (Sigma-Aldrich HPA038497, specificity confirmed by shRNA-mediated knockdown); anti-KAT8 (Santa Cruz Biotechnology INC sc-271691) and anti-AcH4K16 (Abcam ab109463) (Table 1) (26,27). Images were acquired with a NikonDXN1200F digital camera controlled by EclipseNet software (version1.20.0 build 61).…”

Mechanisms of Lung Fibrosis Resolution

“…86,88,90 Senescent lung fibroblasts have been reported to resist apoptosis through the epigenetic mechanism of histone modification, resulting in up-regulation of the antiapoptotic gene, Bcl-2, and low expression of the proapoptotic gene, Bax. 91 Although the aged lung is more susceptible to the onset of fibrosis, few studies in the lung or other organs specifically address the capacity for resolution of established fibrosis in aged models. Hecker et al 51 demonstrated that bleomycin-induced fibrosis resolution was impaired in aged mice.…”