Hypermethylation and transcriptional downregulation of the CITED4 gene at 1p34.2 in oligodendroglial tumours with allelic losses on 1p and 19q

Abstract

Deletions of chromosomal arms 1p and 19q are frequent in oligodendroglial tumours and have been associated with sensitivity to radio-and chemotherapy as well as favourable prognosis. By using microarray-based expression profiling, we found that oligodendroglial tumours with 1p and 19q losses showed significantly lower expression of the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 4 gene (CITED4) at 1p34.2 as compared to tumours without 1p and 19q losses. Mutational analysis showed no CITED4 mutations in gliomas. However, 1p and 19q losses as well as low expression of CITED4 transcripts were significantly associated with hypermethylation of the CITED4-associated CpG island. In line with the latter finding, treatment of CITED4 hypermethylated glioma cell lines with 5-aza-2 0 -deoxycytidine and trichostatine A resulted in a marked increase of the CITED4 transcript levels. Furthermore, CITED4 hypermethylation was significantly associated with longer recurrence-free and overall survival of patients with oligodendroglial tumours. Taken together, our results indicate that CITED4 is epigenetically silenced in the vast majority of oligodendroglial tumours with 1p and 19q deletions and suggest CITED4 hypermethylation as a novel prognostic marker in oligodendroglioma patients.

Downregulation of PRDX1 by promoter hypermethylation is frequent in 1p/19q-deleted oligodendroglial tumours and increases radio- and chemosensitivity of Hs683 glioma cells in vitro

“…Thereby, we identified a set of candidate genes showing significantly reduced mRNA expression levels in 1p/19q-deleted as compared with 1p/19q-intact tumours (Tews et al, 2006). These included the CITED4 gene at 1p34.2 (Tews et al, 2007) as well as several other genes, among which the peroxiredoxin 1 (PRDX1) gene appeared as a particular promising candidate because (i) it was independently identified in a proteomic screen of lowgrade oligodendroglial tumours (Grzendowski et al, 2010), (ii) was reported to have tumour-preventive functions (Neumann et al, 2003) and (iii) was linked to radiotherapy response of cancer cells Zhang et al, 2008). Here, we report on the mechanism leading to the frequent downregulation of PRDX1 mRNA and proteins in 1p/19q-deleted gliomas and provide first evidence for a role of peroxiredoxin 1 in the response of Hs683 glioma cells to TMZ and ionizing irradiation.…”

Aberrant DNA methylation but not mutation of CITED4 is associated with alteration of HIF-regulated genes in breast cancer

“…MS-HRM primers were designed in the region to match the region that was previously reported to be methylated for CITED4 by Tews et al [13]. The MS-HRM primers were CITED4-F 5 0 -GGGGAAGTTTCGTTTTT GGGTATAAG-3 0 and CITED4-R 5 0 -ACCGCAACCT AAAATCACAAAAACC-3 0 .…”

Metabolic regulation of myocardial adaptation to exercise.

“…This could be significant because Cited4 is epigenetically regulated whereby hypermethylation of its CpG island causes lower expression. 244 Our results are in line with the general consensus showing that altered metabolism regulates the epigenetic landscape. [321][322][323] While additional work establishing the mechanistic link between metabolism and epigenetics is required, our results provide new insights into the regulation of gene expression via metabolism.…”

“…244 While our data do not address this mechanism, they suggest that low glycolytic rates could prevent such methylation events, thereby permitting Cited4 transcription, especially when appropriate stimuli are present.…”