Regulation of MHC class II expression in glioma cells by class II transactivator (CIITA)

Abstract

We first classified 12 malignant glioma cell lines into three different groups (types 1-3) with respect to major histocompatibility complex (MHC) class II expression and analyzed each group based on the different expression status of the class II transactivator (CIITA) gene. Glioma type 1 (2 of 12) showed constitutive expression of all class II molecules that might be mediated by activation of B cell-specific CIITA promoter III. Glioma type 2 represented the major phenotype (66.7 %) of malignant glioma cell lines, and MHC class II expression was induced by interferon-gamma (IFN-gamma) in this phenotype. Analysis of glioma tissue samples revealed that CIITA promoter IV was detected in 9 of 11 patients (81.8%); however, promoter III was only in two (18.2%). Moreover, cultured glioma cells obtained from a fresh tumor sample upregulated expression of CIITA and class II molecules in the presence of IFN-gamma, strongly suggesting that glioma type 2 might be predominant in glioma tissues. Glioma type 3 (2 of 12) showed CIITA transcripts but loss of MHC class II expression even in the presence of IFN-gamma. In addition, we determined that the constitutive MHC class II expression in the glioma cell lines (type 1) was the result of transcriptional activation of the CIITA gene. This phenomenon was mediated by global histone acetylation over 6 kb upstream from the transcriptional start site of CIITA promoter III. Moreover, stable transfection of CIITA promoter IV as well as promoter III into MHC class II inducible cell lines restored the constitutive expression of all class II molecules. These studies lay the foundation to understand the molecular basis for the expression of class II molecules in gliomas.

Regulatory landscape and clinical implication of MBD3 in human malignant glioma

“…Five major HLA-encoding regions exist: HLA-DM, HLA-DO, HLA-DP, HLA-DQ, and HLA-DR. It has been demonstrated that MHC class II molecules could be constitutively expressed in glioma cells and their level is negatively associated with the tumor invasion and malignancy [13, 16, 17]. As shown in Figure 4B, in comparison with low-grade glioma, GBM has a significantly lower transcription in almost all of the HLA components.…”

“…We hypothesized that one intermediate mechanism accounting for this MBD3-induced massive modulation was through the MHC class II transactivator (CIITA) gene as it exhibited the same reduction trend in the array results. Transcription of CIITA is subjected to epigenetic inactivation, especially by DNA methylation in the promoter IV region [16, 18, 19]. MBD3, in the context of Mi-2/NuRD complex, is involved in maintenance of a hypomethylated state at its occupancy site and thus can facilitate gene expression.…”

A fresh look at an old story: revisiting HLA class II antigen expression by melanoma cells

“…Second, epigenetic mechanisms, such as hypermethylation of the CIITA promoter IV [112] and/or modification of chromatin structure by histone deacetylation [113], may result in defective CIITA expression in both uveal [59] and cutaneous melanoma [94] cells. The latter mechanism is not unique to melanoma as it is also the cause of defective CIITA expression in cell lines derived from carcinomas of the breast [65], stomach [104,114], colon [104,114,115] and cutaneous epithelia [113], as well as from leukemia [116] and neuroblastoma [117]. Lastly, the identification of defects in IFN-γ or Janus kinase-signal transducer and activator of transcription signaling pathways, which regulate CIITA transcription [27], in some cutaneous melanoma [94,118], gastric carcinoma [119], colon adenocarcinoma [101] and leukemic [101] cells, suggests that dysregulation of CIITA transcription may result in a lack of HLA class II antigen expression.…”

HLA antigen changes in malignant cells: epigenetic mechanisms and biologic significance

“…It is thought that CpG dinucleotide methylation of CIITA promoter IV DNA as well as histone deacetylation severely impair recruitment of transcription factors such as IRF-1, Stat-1 and USF-1 to CIITA-PIV, thereby reducing CIITA transcription [86]. The above mechanism has been documented in cell lines derived from carcinoma of breast [15], stomach [87,88], colon [22,88], cervix [85], cutaneous epithelia [89] as well as from T cell leukemia [90], neuroblastoma [91], teratocarcinoma [18], choriocarcinoma [18], and uveal and cutaneous melanoma [14]. More recent studies have suggested that Blimp-1, a zinc-finger DNA-binding protein, recruits a co-repressor complex containing HDAC to the CIITA promoter and this may be responsible for the failure of the plasma cells and related tumors to express HLA class II [92].…”