HDAC2 and 7 down-regulation induces senescence in dermal fibroblasts

Abstract

Originally simply reported to be in a stable and irreversible growth arrest in vitro , senescent cells are now clearly associated with normal and pathological ageing in vivo . They are characterized by several biomarkers and changes in gene expression that may depend on epigenetic factors, such as histone acetylation, involving a balance between histone acetyltransferases (HATs) and histone deacetylases (HDACs). In this study, we investigate the expression and the role of HDACs on the senescent phenotype of dermal fibroblasts. We report that during replicative senescence, most canonical HDACs are less expressed. Moreover, treatment with SAHA, a histone deacetylase inhibitor (HDACi) also known as Vorinostat, or the specific downregulation of HDAC2 or HDAC7 by siRNA, induces the appearance of senescence biomarkers of dermal fibroblasts. Conversely, the ectopic re-expression of HDAC7 by lentiviral transduction in pre-senescent dermal fibroblasts extends their proliferative lifespan. These results demonstrate that HDACs expression can modulate the senescent phenotype, highlighting their pharmaceutical interest in the context of healthy ageing.

HDACs and the Epigenetic Plasticity of Cancer Cells: Target the Complexity

“…The anti-senescence role of HDAC4 is explained by competition with AP1/P300 to enforce H3K27ac status at selected enhancers and super-enhancers that orchestrate the senescence program . HDAC7 has also been reported to be modulated during senescence and its downregulation promotes senescence in fibroblasts (Warnon et al, 2021). Similarly, HDAC5 may also act as a senescence antagonist.…”

The Potential of Senescence as a Target for Developing Anticancer Therapy

“…This implies that AURK inhibitors can also induce senescence in a p53-independent way. The inhibition of HDAC2 or HDAC7 induced senescence by increasing the expression of p16 and p21 in dermal fibroblasts [ 33 ]. The downregulation of DNA methyl transferase 2 causes telomere shortening and senescence [ 34 ].…”

“…SAHA (vorinostat), an HDACi, or the specific downregulation of HDAC2 or HDAC7 by siRNA, induced senescence in dermal fibroblasts by increasing the expression of IL-6, IL-8, MMP-1/-3, and IL-1β [ 33 ]. The ectopic overexpression of HDAC7 by lentiviral transduction in pre-senescent dermal fibroblasts extended their proliferative lifespan [ 33 ]. These reports suggest that HDACs could inhibit senescence.…”

Cellular senescence and the blood–brain barrier: Implications for aging and age-related diseases

“…Senescent mouse BECs showed increased BBB leakage as evidenced by reduced transendothelial electrical resistance, and increased permeability to albumin in comparison to non-senescent/ low passage mouse BECs. [115][116][117] Senescence can also be induced in vitro through physical or chemical stressors, such as ionizing radiation, chemotherapeutics, or oxidative stress and specific protocols have been described to do so. [115][116][117] Importantly, senescence is a slow process, taking about three to seven days to develop in response to stressors.…”