Insights into the Nanog gene: A propeller for stemness in primitive stem cells

Abstract

Self-renewal and pluripotency are two major characteristics of embryonic stem cells (ESCs) that allow ESCs to maintain stem cell population, and differentiate into multiple types of adult tissues. Nanog is the key transcription factor that controls both self-renewal and pluripotency of ESCs. Similarly, cancer stem cells (CSCs) are capable of preserving population and initiating new tumor development by self-renewal. Expression of Nanog family proteins can be increased in many types of cancer which is correlated with tumor outcomes. In this review we summarized the recent understanding of the roles and mechanisms of Nanog in ESC regulation under physiological conditions. In addition, we describe the function of Nanog family proteins in different types of cancer, and the association of Nanog with clinical outcomes. Taken together, Nanog proteins are central regulators controlling both ESCs and CSCs, and are considered as a prognostic marker in many types of cancer. These findings supported the possibility of novel therapeutic potentials of Nanog against cancers.

Keywords: Nanog; cancer recurrence; cancer stem cell; embryonic stem cell; metastasis; pluripotency.

Figure 1

Genomic and protein structures of Nanog genes. (A-B) Genomic structures of Nanog1 (A), and Nanogp8 gene (B). The 2 genes both have 4 exons (E) with a 915-bp ORF. NanogP8 is a retrotransposed gene and thus lacks introns, whose sizes in Nanog1 are indicated. The 2 genes have identical 5′-UTRs except the first ~18-bp, which are unique to each gene (marked by a green and red rectangle). The 2 genes also have very similar 3′-UTRs except for the ~20-bp sequence in the Nanog1 3′-UTR (A). The specific sequences in this region were used to design Nanog1/NanogP8-specific PCR primers. TSS, transcriptional start site. (C) Protein structure of Nanog1 protein. Nanog1 protein consists of an N-terminal “interference” domain (ND), homeodomain (H) important for DNA binding, and a C-terminal domain containing 2 subdomains (CD1 and CD2, responsible for transactivation) and a tryptophan-rich domain (WRD) involved in dimerization. The red line in CD2 indicates the conserved amino acid change (Q253H) in NanogP8 protein.

Figure 2

Nanog regulates self-renewal and pluripotency in pluripotent stem cells. Nanog is capable of regulating self-renewal and pluripotency in inner cell mass (ICM)-derived embryonic stem cells (ESCs). Nanog, in combination with Oct4, Sox2 and Lin28, can be utilized to induce efficient reprogramming in fibroblasts to generate induced pluripotent stem cells (iPSCs).

Figure 3

Roles of Nanog in Cancer. Collaborating with c-myc, Oct4 and Sox2, Nanog regulates self-renewal, proliferation, epithelial-mesenchymal transition (EMT) and metastasis of cancer cells through miscellaneous pathways. Nanog expression is regulated by c-Jun/β-catenin and can be suppressed by p53. Consistently, miR-21 can activate Nanog pathway by direct inhibition of p53.