Pluripotency factor Nanog is tumorigenic by deregulating DNA damage response in somatic cells

Abstract

The pluripotency gene Nanog is not expressed in normal adult tissues but is overexpressed in some human cancers. However, the tumorigenic roles of Nanog remain unclear. The ectopic expression of Nanog is not sufficient to induce spontaneous tumors in mice but can promote metastasis of established tumors by activating the expression of metastatic genes. The expression of Nanog in mouse skin activates tumor suppressor p53, leading to the differentiation of epidermal stem cells. In the absence of p53, Nanog induces spontaneous squamous cell carcinoma, identifying a novel role of Nanog in tumorigenesis. Therefore, the induction of p53 and differentiation in Nanog-expressing skin suppresses the tumorigenic activities of Nanog, which include the induction of DNA double-stranded break damage. Notably, Nanog interacts with the KRAB-associated protein 1 (KAP1) and inhibits its sumoylation activity, impairing KAP1-mediated chromatin remodeling, which is important for efficiently activating DNA damage response. In summary, Nanog is an oncogene with multiple roles in promoting tumorigenesis and metastasis.

NANOG reprograms prostate cancer cells to castration resistance via dynamically repressing and engaging the AR/FOXA1 signaling axis

“…A causal role of NANOG in tumorigenesis has been demonstrated not only by loss- and gain-of-function studies in cancer cells [1, 3, 9] but also by, recently, CRISPR/Cas9-mediated knockout [31] and genetic mouse model [28, 32, 33,34] studies. In addition to constitutive expression of NANOG in a small subset of cancer cells, NANOG may also be induced by tumor microenvironments such as inflammatory cytokines and hypoxia [27, 30, 35].…”

IDO1 Maintains Pluripotency of Primed Human Embryonic Stem Cells by Promoting Glycolysis

“…Glycolysis is important to maintain the pluripotency, and the metabolic switch from glycolysis to oxidative phosphorylation is required for ESC differentiation . Accumulating evidence has suggested that pluripotency factors such as NANOG, OCT4, and SALL4 play important roles in maintaining glycolysis and genomic stability in ESCs . In this study, we identify IDO1 as a key regulator of pluripotency and metabolism in hESCs.…”

The roles of NANOG in tumorigenesis

“…Consistent with previous findings, the expression of Nanog in skin cells activates tumor suppressor p53, leading to suppression of the oncogenic activity of Nanog. 9 In addition, hair follicle stem cells were depleted while there was an increase in epidermal differentiation markers. 9 It seems that Nanog-expressing stem cells, which can be potential tumor initiation (stem) cells, are removed by differentiation in both cases.…”

“…9 In addition, hair follicle stem cells were depleted while there was an increase in epidermal differentiation markers. 9 It seems that Nanog-expressing stem cells, which can be potential tumor initiation (stem) cells, are removed by differentiation in both cases. This Nanog-induced differentiation could inhibit initiation of the 2-stage skin tumorigenesis observed in previous studies.…”

“…This interaction inhibits regulatory modification of KAP1 by sumoylation, resulting in the accumulation of DNA damage and activation of DDR signaling, including p53. 9 The increased differentiation and apoptosis in the skin of Nanog-TG mice is ameliorated in the p53-null background, together with the accelerated accumulation of DNA damage. 9 This may be the mechanism by which the oncogenic role of Nanog is regulated by tumor stage or p53 status.…”