Glioma is the most common primary tumor in central nervous system neoplastic diseases, often manifested as high malignancy, high recurrence rate, high disability rate, and low survival time [1,2]. The incidence of glioma is approximately 3–6 per 0.1 million people, accounting for about 75% of adult primary malignant brain tumors [3,4]. Glioblastoma multiforme is a WHO grade IV glioma, accounting for about 57.3% of glioma and 48.3% of all malignant brain tumors [3]. Surgical resection remains the mainstay strategy of glioma treatment [5]. Diffuse glioma is common, and it affects the surrounding brain tissues. No clear boundary between the glioma tissue and the surrounding normal tissue is a difficulty in treatment for glioma [6]. Therefore, it is difficult to completely remove tumor cells by surgical resection. Despite discovering of many new molecular markers of glioma, the effective strategies were not improved significantly [7,8]. In-depth exploration on the mechanism related to the occurrence and development of glioma is of great significance for the treatment of glioma.

The occurrence and development of glioma are regulated by epigenetics [9]. Inverted CCAAT box Binding Protein of 90 kDa (ICBP90), an up-regulated oncogene during tumorigenesis, plays an important role in cell epigenetic modification [10,11]. ICBP90 protein consists of the UBL domain, Tudor domain, PHD domain, SRA domain, and RING domain [12]. The SRA domain specifically binds to hemi-methylated CpG islands (mCpG) and recruits DNA methylation transferase 1 (DNMT1) around DNA replication forks to maintain DNA methylation levels [13,14]. ICBP90 is involved in tumor cell proliferation, apoptosis, migration, and invasion by regulating DNA methylation and histone modification [15,16]. ICBP90 over-expression led to hyper-methylation of the promoter of tumor suppressor genes (TSGs), and thereby suppressed their transcription and down-regulated their expression levels [17]. Boukhari et al. [15] found that ICBP90 up-regulation was related to silencing of TSGs in glioblastoma multiforme. We found that ICBP90 was significantly higher in the glioma tissues than in the control brain tissues. However, the regulatory mechanism of ICBP90 in glioma remains unclear.

Wnt/β-catenin pathway was implicated in malignant glioma [18]. Dickkopf 3 homolog (DKK3), also known as reduced expression in immortalized cells (REIC), is a member of the Dickkopf family and an antagonist of wnt/β-catenin pathway [19]. DKK3 has been identified as a tumor suppressor gene in glioma [20]. Recent results showed that ICBP90 knockdown inhibited DNA hyper-methylation and activated the expression of TSGs in colorectal cancer (CRC) [21]. ICBP90 induced the methylation of TXNIP promoter and down-regulated TXNIP expression by binding to the CCAAT box of TXNIP promoter region in cervical cancer [17]. CpG islands and the ICBP90 binding site are found in the promoter region of DKK3, however, the relationship between ICBP90 and DKK3 in glioma has not previously been examined.

Herein, we investigated the epigenetic regulation of DKK3 by ICBP90 in glioma. To identify the effect of ICBP90 on the malignant behavior and chemotherapy sensitivity, we constructed ICBP90-over-expressed or ICBP90-silenced glioma cells. The binding of ICBP90 to the DKK3 promoter was confirmed by chromatin immunoprecipitation (ChIP), and the regulation of DKK3 promoter methylation by ICBP90 was confirmed by methylation-specific polymerase chain reaction (MSP). Our study suggests that ICBP90 probably contributes to tumorigenesis and inhibits cis-platinum (DDP) sensitivity via inducing DKK3 promoter methylation.