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.
Highlights
Ageing is characterized by a general slowdown of the physiological functions of the organism, predisposing to the appearance of age-related pathologies such as cancer, cardiovascular diseases and neurological disorders
First detected in vitro, are clearly associated with normal and pathological ageing in vivo [1, 2]. This has been highlighted thanks to the identification of senescent cells monitored by several biomarkers including the irreversible growth arrest related to the expression of cyclin-dependent kinase inhibitors p16INK4A and p21WAF-1, a significant increase in cell size, senescence-associated βgalactosidase activity (SA-βgal), persistent DNA damage, senescence-associated heterochromatin foci (SAHF), resistance to apoptosis, and the expression of a particular secretome composed of inflammatory cytokines, chemokines, growth factors and proteases and referred to as the senescenceassociated secretory phenotype (SASP) [3, 4]
To investigate whether the expression of other histone deacetylases (HDACs) is modified during replicative senescence of human dermal fibroblasts (HDFs), we monitored the protein levels of HDACs 1-7 in three HDFs strains: AG04431 human dermal fibroblasts and normal HDFs isolated from 57-yrs-old (NHDF1) and 3-yrs-old (NHDF2) donors
Summary
Ageing is characterized by a general slowdown of the physiological functions of the organism, predisposing to the appearance of age-related pathologies such as cancer, cardiovascular diseases and neurological disorders. First detected in vitro, are clearly associated with normal and pathological ageing in vivo [1, 2]. This has been highlighted thanks to the identification of senescent cells monitored by several biomarkers including the irreversible growth arrest related to the expression of cyclin-dependent kinase inhibitors p16INK4A and p21WAF-1, a significant increase in cell size, senescence-associated βgalactosidase activity (SA-βgal), persistent DNA damage, senescence-associated heterochromatin foci (SAHF), resistance to apoptosis, and the expression of a particular secretome composed of inflammatory cytokines, chemokines, growth factors and proteases and referred to as the senescenceassociated secretory phenotype (SASP) [3, 4]. The SASP composition is dependent on the cell type, the senescence inducer and the time spent since the senescence-inducing event [7, 8]
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