Abstract
Stemness and reprogramming involve transcriptional master regulators that suppress cell differentiation while promoting self-renewal. A distinguished example thereof is SOX2, a high mobility group (HMG)-box transcription factor (TF), whose subcellular localization and turnover regulation in embryonic, induced-pluripotent, and cancer stem cells (ESCs, iPSCs, and CSCs, respectively) is mediated by the PI3K/AKT/SOX2 axis, a stem cell-specific branch of the PI3K/AKT signaling pathway. Further effector functions associated with PI3K/AKT induction include cell cycle progression, cellular (mass) growth, and the suppression of apoptosis. Apoptosis, however, is a central element of DNA damage response (DDR), where it provides a default mechanism for cell clearance when DNA integrity cannot be maintained. A key player in DDR is tumor suppressor p53, which accumulates upon DNA-damage and is counter-balanced by PI3K/AKT enforced turnover. Accordingly, stemness sustaining SOX2 expression and p53-dependent DDR mechanisms show molecular–functional overlap in PI3K/AKT signaling. This constellation proves challenging for stem cells whose genomic integrity is a functional imperative for normative ontogenesis. Unresolved mutations in stem and early progenitor cells may in fact provoke transformation and cancer development. Such mechanisms are also particularly relevant for iPSCs, where genetic changes imposed through somatic cell reprogramming may promote DNA damage. The current review aims to summarize the latest advances in the understanding of PI3K/AKT/SOX2-driven stemness and its intertwined relations to p53-signaling in DDR under conditions of pluripotency, reprogramming, and transformation.
Highlights
SRY homology box 2 (SOX2) is a transcriptional modulator imperative to the induction and maintenance of stem cells [1,2]
The PI3K/AKT/SOX2 axis provides an attractive lever to improve reprogramming efficacy and to address some of the safety concerns associated with iPSC induction
This axis may offer a molecular mechanism for therapeutic intervention in SOX2+ cancers and, against SOX2+ CSCs
Summary
SRY homology box 2 (SOX2) is a transcriptional modulator imperative to the induction and maintenance of stem cells [1,2]. A given cell qualifies as a “stem cell” if it meets the following functional criteria: stem cells persist in a largely undifferentiated, often dormant physiological default state unless triggered to (1) self-renew and (2) differentiate supporting tissue (re)generation in ontogenesis, homeostasis, and wound healing This accounts for a wide diversity in stem cell classes, in which SOX2 is a recurrent molecular hallmark. Consistent with the notion that developmental pathways have transforming potential when inadequately or untimely induced, dysregulated SOX2 expression was reported as a molecular hallmark in human cancer [13,14]. This includes testicular germ cell tumors [15], as well as various carcinomas and gliomas/glioblastomas, that match SOX2’s lineage commitment. Various lines of evidence define SOX2 as a critical co-inductor and/or maintenance factor in healthy, diseased, and induced stem cell settings
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