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

Abstract

Deletions of chromosomal arms 1p and 19q are frequent in oligodendroglial tumours and linked to radio-and chemotherapy response as well as longer survival. The molecular mechanisms underlying this clinically important association are as yet unknown. Here, we studied the peroxiredoxin 1 (PRDX1) gene at 1p34.1 for promoter methylation and expression in primary gliomas and investigated its role in radio-and chemosensitivity of glioma cells in vitro. In total, we screened primary glioma tissues from 93 patients for methylation of the 5 0 -CpG island of PRDX1 by sodium bisulfite sequencing. PRDX1 mRNA and protein expression levels were determined in subsets of the tumours by quantitative PCR and western blot analysis, respectively. PRDX1 hypermethylation and reduced expression were frequently detected in oligodendroglial tumours and secondary glioblastomas, but not in primary glioblastomas. In oligodendroglial tumours, both PRDX1 hypermethylation and reduced mRNA expression were significantly associated with 1p/19q-deletion. Stable knockdown of PRDX1 by lentiviral transduction of shorthairpin (sh)RNA constructs significantly increased apoptosis and reduced cell viability of Hs683 glioma cells exposed to ionizing irradiation or temozolomide in vitro. Taken together, our findings indicate that epigenetic silencing of PRDX1 is frequent in 1p/19q-deleted oligodendroglial tumours and likely contributes to radioand chemosensitivity of these tumours.

Redox proteomics reveal stress responsive proteins linking peroxiredoxin-1 status in glioma to chemosensitivity and oxidative stress

“…An effect of PRDX1 expression upon chemo-and radio-resistance has also been shown in Hs683 glioma cells: lentiviral mediated knockdown of PRDX1 sensitizes the cells to irradiation and treatment with temozolomide [8] leading to enhanced apoptosis which supports our findings.…”

“…For this, we used a BCNU concentration near the EC50 as determined for A172 cells transfected with the control vector (7.9 μM, 95% confidence interval 7.3-8.5 μM). These results are in line with observations in oligodendroglial tumor patients showing a better prognosis and response to chemotherapy if they carry a deletion on the chromosomal arms 1p/19q which is associated with a reduced PRDX1 protein level [5,6,29,30]. Nevertheless, in a recent study hypermethylation of PRDX1 was not verified as prognostic marker in elderly patients with malignant astrocytoma [31].…”

“…In a proteome study comparing oligoastrocytoma with and without 1p/19q deletion, we previously noticed a lower abundance of peroxiredoxin-1 (PRDX1) in tumors with 1p/19q deletion [6] which has also been shown for a group of different glioma on mRNA level using microarray based expression profiling [7]. Both the localization of the PRDX1 gene at 1p34.1 and frequent hypermethylation of 5′ CpG islands of the PRDX1 gene, as shown for oligodendroglial tumours and secondary glioblastomas, might contribute to the reduced expression of PRDX1 in gliomas [8].…”

Epigenetic regulation of peroxiredoxins: Implications in the pathogenesis of cancer

“…In oligodendroglial tumors, methylation analysis revealed that PRX I-associated CpG island was frequently hypermethylated in 1p/19q-deleted primary tumors and expressed reduced PRX I mRNA transcripts. 41 In addition, DNA hypermethylation and H3 histone hypoacetylation, also correlated with repressed tumor suppressor PRX II expression in acute myeloid leukemia (AML) and classic Hodgkin lymphoma. 58,59 Histone modification…”

“…Moreover, PRX I silencing by promoter methylation has been reported to increase chemotherapy and radiation sensitivity of Hs683 glioma cells in vitro. 41 It would appear that downregulation of PRXs sensitizes chemo-and radio-resistant cells, thereby highlighting the importance of PRXs in radiation and drug sensitivity.…”