Abstract
SummaryCellular senescence is a permanent proliferative arrest triggered by genome instability or aberrant growth stresses, acting as a protective or even tumor‐suppressive mechanism. While several key aspects of gene regulation have been known to program this cessation of cell growth, the involvement of the epigenetic regulation has just emerged but remains largely unresolved. Using a systems approach that is based on targeted gene profiling, we uncovered known and novel chromatin modifiers with putative link to the senescent state of the cells. Among these, we identified SETD8 as a new target as well as a key regulator of the cellular senescence signaling. Knockdown of SETD8 triggered senescence induction in proliferative culture, irrespectively of the p53 status of the cells; ectopic expression of this epigenetic writer alleviated the extent doxorubicin‐induced cellular senescence. This repressive effect of SETD8 in senescence was mediated by directly maintaining the silencing mark H4K20me1 at the locus of the senescence switch gene p21. Further in support of this regulatory link, depletion of p21 reversed this SETD8‐mediated cellular senescence. Additionally, we found that PPARγ acts upstream and regulates SETD8 expression in proliferating cells. Downregulation of PPARγ coincided with the senescence induction, while its activation inhibited the progression of this process. Viewed together, our findings delineated a new epigenetic pathway through which the PPARγ‐SETD8 axis directly silences p21 expression and consequently impinges on its senescence‐inducing function. This implies that SETD8 may be part of a cell proliferation checkpoint mechanism and has important implications in antitumor therapeutics.
Highlights
The process of biological aging is described as senescence, through which the function of a mature organism gradually deteriorates, leading to mortality
To further strengthen the notion that PPARc is directly involved in SETD8 regulation during cellular senescence, we aimed to demonstrate that this transcriptional role is mediated through promoter binding
Via ChIP-qPCR assay on the PPARcoverexpressing cells, we found that the chromatin binding of PPARc increases on SETD8 promoter upon ectopic expression (Fig. 6H)
Summary
The process of biological aging is described as senescence, through which the function of a mature organism gradually deteriorates, leading to mortality. One aspect of the senescence is ‘cellular senescence’, which was initially observed in cultured fibroblasts that, upon finite number of cell cycle, irreversibly cease to proliferate—a state called replicative senescence or the Hayflick limit. In addition to this replicative senescence that is attributed to telomere shortening (d’Adda di Fagagna et al, 2003), senescence could be induced by DNAdamaging agents or aberrant oncogene activation, thereby acting as a protective response (Halazonetis et al, 2008; Gorgoulis & Halazonetis, 2010). The functional relevance of this chromatin-based mechanism has not been characterized in depth
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