Abstract
NANOG is a key transcription factor required for maintaining pluripotency of embryonic stem cells. Elevated NANOG expression levels have been reported in many types of human cancers, including lung, oral, prostate, stomach, breast, and brain. Several studies reported the correlation between NANOG expression and tumor metastasis, revealing itself as a powerful biomarker of poor prognosis. However, how NANOG regulates tumor progression is still not known. We previously showed in medaka fish that Nanog regulates primordial germ cell migration through Cxcr4b, a chemokine receptor known for its ability to promote migration and metastasis in human cancers. Therefore, we investigated the role of human NANOG in CXCR4-mediated cancer cell migration. Of note, we found that NANOG regulatory elements in the CXCR4 promoter are functionally conserved in medaka fish and humans, suggesting an evolutionary conserved regulatory axis. Moreover, CXCR4 expression requires NANOG in human glioblastoma cells. In addition, transwell assays demonstrated that NANOG regulates cancer cell migration through the SDF1/CXCR4 pathway. Altogether, our results uncover NANOG-CXCR4 as a novel pathway controlling cellular migration and support Nanog as a potential therapeutic target in the treatment of Nanog-dependent tumor progression.
Highlights
Murine Nanog directly regulates the expression of Oct4, Sall1 and Sall4, and regulates itself in mouse embryonic stem cells (ESC) by binding to their promoter regions [41]
To study whether the gene-targeted profile by Nanog in medaka fish resembles that of mammals we performed the chromatin immunoprecipitation assay (ChIP) in medaka fish embryos with Nanog specific antibodies
Our results obtained by ChIP showed that Nanog binds to the regulatory sequences of
Summary
The homeodomain-containing transcription factor Nanog is a crucial determinant of pluripotency [1,2,3,4]. Experiments for the reprogramming of somatic cells to ground state pluripotency revealed the key role of Nanog at different levels of this process. Nanog is dispensable, it is necessary for dedifferentiated intermediates to reach the ground state pluripotency [5]. In this regard, Nanog intervenes by overcoming reprogramming barriers and enabling self-renewal of stem cells [6,7]. In contrast to most genes associated with pluripotency, Nanog shows poor sequence identity among species, but is functionally conserved in vertebrates, suggesting that control of pluripotency resides in a unique DNA responsive element [8,9]
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