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.