Transcriptional regulation of CDKN2A/p16 by sirtuin 7 in senescence

Abstract

cell senescence is a state of limited cell proliferation during a stress response or as part of a programmed process. When a senescent cell stops dividing, maintaining metabolic activity contributes to cellular homeostasis maintenance. in this process, the cell cycle is arrested at the G0/G1 phase. p16 inK4a protein is a key regulator of this process via its cyclin-dependent kinase inhibitor (cdKi) function. CDKI 2A (CDKN2A)/p16 gene expression is regulated by dna methylation and histone acetylation. Sirtuins (SirTs) are nicotinamide dinucleotide (nad + )-dependent deacetylases that have properties which prevent diseases and reverse certain aspects of aging (such as immune, metabolic and cardiovascular diseases). By performing quantitative Pcr, Western blot, chiP, and sirnas assays, in this study it was demonstrated that CDKN2A/p16 gene transcriptional activation and repression were accompanied by selective deposition and elimination of histone acetylation during the senescence of MRC5 cells. Specifically, significant H3K9Ac and H3K18Ac enrichment in cells with a senescent phenotype concomitant with CDKN2A/p16 gene overexpression was demonstrated compared with the non-senescent phenotype. Furthermore, the presence of H3K18Ac in deacetyl-transferase SIRT7 knockdown Mrc5 cells allowed CDKN2A/p16 promoter activation. These results suggested that SIRT7 served as a critical component of an epigenetic mechanism involved in senescence mediated by the CDKN2A/p16 gene.

Predictive potential of cuproptosis-related genes in multiple myeloma: Comprehensive analysis based on bone marrow whole-genome sequencing

“…Surprisingly, there was a contrasting pattern observed in the mRNA and protein expression of CDKN2A. The discrepancy implies that CDKN2A might undergo posttranscriptional epigenetic alterations in MM tumors and senescence, potentially including promoter methylation and regulation of histone acetylation [41,42] . As a result, we hypothesized that MM may make CDKN2A more prone to post-transcriptional epigenetic alterations, leading to decreased mRNA expression and impacting the progression of the disease.…”

The potential for senotherapy as a novel approach to extend life quality in veterinary medicine

“…Preluding gene expression, epigenetic regulators modulate transcription senescent markers and SASP factors ( 41 , 42 ). This was shown in human stromal cells when histone H3-specific demethylase KDM4 was found to potentiate senescent markers such as p16 INK4a , p21 CIP1 , and CXCL8 ( 43 ).…”