Abstract
Activation of the stem cell transcriptional circuitry is an important event in cancer development. Although cancer cells demonstrate a stem cell-like gene expression signature, the epigenetic regulation of pluripotency-associated genes in cancers remains poorly understood. In this study, we characterized the epigenetic regulation of the pluripotency-associated genes NANOG, OCT4, c-MYC, KLF4, and SOX2 in a variety of cancer cell lines and in primary tumor samples, and investigated the re-activation of pluripotency regulatory circuits in cancer progression. Differential patterns of DNA methylation, histone modifications, and gene expression of pluripotent genes were demonstrated in different types of cancers, which may reflect their tissue origins. NANOG promoter hypomethylation and gene upregulation were found in metastatic human liver cancer cells and human hepatocellular carcinoma (HCC) primary tumor tissues. The upregulation of NANOG, together with p53 depletion, was significantly associated with clinical late stage of HCC. A pro-metastatic role of NANOG in colon cancer cells was also demonstrated, using a NANOG-overexpressing orthotopic tumor implantation mouse model. Demethylation of NANOG promoter was observed in CD133+high cancer cells. In accordance, overexpression of NANOG resulted in an increase in the population of CD133+high cells. In addition, we demonstrated a cross-regulation between OCT4 and NANOG in cancer cells via reprogramming of promoter methylation. Taken together, epigenetic reprogramming of NANOG can lead to the acquisition of stem cell-like properties. These results underscore the restoration of pluripotency circuits in cancer cells as a potential mechanism for cancer progression.
Highlights
Epigenetic changes are considered as potent surrogates to mutations in the deregulation of growth-promoting genes and tumor-suppressor genes [1,2]
While overexpression of OCT4, SOX2, KLF4 and c-MYC genes induce pluripotency in somatic cells leading to the generation of embryonic stem cell (ESC)-like induced pluripotent stem cells [6,7,8], it is interesting to note that the ESC-like transcriptional program is often activated in diverse human epithelial cancers [9,10]
Epigenetic regulations of pluripotent gene expression We focused on the pluripotent gene expression in two cancer cell lines, 97L and HCT116, which showed opposite patterns of DNA methylation. quantitative real time PCR (qRT-PCR) analysis demonstrated higher expression of NANOG, OCT4 and c-MYC genes in 97L cells but not in HCT116 cells, when compared to control L02 and PLC cells (Figure 2A–C; Figure S5A–C in File S1), suggesting the expression of these genes is negatively regulated by DNA methylation
Summary
Epigenetic changes are considered as potent surrogates to mutations in the deregulation of growth-promoting genes and tumor-suppressor genes [1,2]. While overexpression of OCT4, SOX2, KLF4 and c-MYC genes induce pluripotency in somatic cells leading to the generation of embryonic stem cell (ESC)-like induced pluripotent stem cells (iPSCs) [6,7,8], it is interesting to note that the ESC-like transcriptional program is often activated in diverse human epithelial cancers [9,10]. Such an ESC-like gene module was associated with disease progression, e.g. metastasis, and early mortality of breast cancer [9] and bladder cancer [11]. Recent studies have demonstrated that iPSCs retain epigenetic memory, such as DNA methylation signature, from their tissue origins [13,14], indicating the importance of epigenetic regulation in cell fate reprogramming and tumorigenesis [15,16]
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