Abstract
The role of sirtuins (SIRTs) in cancer biology has been the focus of recent research. The similarities between underlying pathways involved in the induction of pluripotent stem cells and transformation of cancer cells revealed the role of SIRTs in cellular reprogramming. Seven SIRTs have been identified in mammals and downregulation of SIRT2 was found to facilitate the generation of primed pluripotent stem cells, such as human induced pluripotent stem cells. Herein, we evaluated the role of SIRT2 in naive pluripotent stem cell generation using murine cells. We found that absolute depletion of SIRT2 in mouse embryonic fibroblasts resulted in a notable reduction in reprogramming efficiency. SIRT2 depletion not only upregulated elements of the INK4/ARF locus, which in turn had an antiproliferative effect, but also significantly altered the expression of proteins related to the PI3K/Akt and Hippo pathways, which are important signaling pathways for stemness. Thus, this study demonstrated that SIRT2 is required for cellular reprogramming to naive states of pluripotency in contrast to primed pluripotency states.
Highlights
Sirtuins (SIRTs) are highly conserved NAD+-dependent deacetylases[1]
We demonstrated the production of functionally competent naive induced pluripotent stem cell (iPSC) with self-renewal capacity that differentiated into three germinal layers both in vitro and in vivo with blastocyst chimera formation, even from SIRT2-knockout (KO) mouse embryonic fibroblasts (MEFs); reprogramming efficiency was significantly low
We examined various murine cells, including pluripotent stem cells such as embryonic stem cells and iPSCs, adipose-derived stem cells as multipotent stem cells, and unipotent somatic cells including MEFs and dermal fibroblasts
Summary
Sirtuins (SIRTs) are highly conserved NAD+-dependent deacetylases[1]. There are seven different SIRTs (SIRT1–SIRT7) with discrete subcellular localizations and distinct functions[2]. Because SIRTs play a key role in maintaining genomic integrity by coordinating cellular responses to various stresses, their aberrant regulation causes tumorigenesis[4]. According to previous studies, overlapping mechanisms control induced pluripotent stem cell (iPSC) production and tumorigenesis[5,6]. A study comparing the Several reports have described a correlation between SIRTs and iPSC reprogramming efficiency. SIRT1 enhances iPSC generation through p53 deacetylation, and is required for proficient post-reprogramming telomere elongation[8,9]. Other SIRTs (SIRT2–SIRT7) have received less attention in this regard;
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