Frequent promoter hypermethylation and transcriptional downregulation of the NDRG2 gene at 14q11.2 in primary glioblastoma

Abstract

The N-myc downstream-regulated gene 2 (NDRG2) at 14q11.2 has been reported to be downregulated in glioblastoma, and NDRG2 overexpression represses glioblastoma cell proliferation in vitro (Deng et al., Int J Cancer 2003;106;342-7). To further address the role of NDRG2 as a candidate tumor suppressor in human gliomas, we analyzed 67 astrocytic tumors (10 diffuse astrocytomas, 11 anaplastic astrocytomas, 34 primary glioblastomas and 12 secondary glioblastomas) for NDRG2 gene mutation, promoter methylation and expression at the mRNA and protein levels. Using real-time reverse transcription PCR analysis, we found decreased NDRG2 mRNA levels in primary glioblastomas as compared to diffuse and anaplastic astrocytomas. Similarly, immunohistochemistry revealed low or absent NDRG2 protein expression in primary glioblastomas. Mutational analysis of the entire NDRG2 coding sequence did not reveal any tumor-associated DNA sequence alterations. However, sequencing of sodium bisulfitemodified DNA identified hypermethylation of the NDRG2 promoter region in 21 of 34 primary glioblastomas (62%). Moreover, NDRG2 promoter hypermethylation was associated with decreased NDRG2 mRNA expression. In contrast to primary glioblastomas, NDRG2 promoter hypermethylation was detected in only 1 of 11 anaplastic astrocytomas (9%) and was absent in 10 diffuse astrocytomas and 12 secondary glioblastomas. Taken together, our data support NDRG2 as a candidate tumor suppressor gene that is epigenetically silenced in the majority of primary glioblastomas, but not in lower grade astrocytomas and secondary glioblastomas.

NDRG4 Is Required for Cell Cycle Progression and Survival in Glioblastoma Cells

“…1A). This finding is in contrast to the reported lower expression level of NDRG2 in neoplastic glioma cells relative to normal nonneoplastic glial cells, an observation fitting with the presumed role of NDRG2 as a tumor suppressor in this context (11,13,14).…”

“…To date, however, NDRG2 is the only NDRG family member that has been studied in the context of GBM cells and astrocytes. NDRG2 mRNA and protein levels are lower in GBM than in normal brain tissue, normal glial cells, and low grade astrocytomas (11)(12)(13)(14), suggesting a tumor suppressive function. Data from experimental and clinical studies support this hypothesis: NDRG2 overexpression inhibits GBM cell proliferation (15), and decreased NDRG2 expression correlates with decreased GBM patient survival (13).…”

NDRG4 is Downregulated in Glioblastoma and Inhibits Cell Proliferation

“…NDRG2 is also described as a tumor suppressor. Compared to normal tissues, NDRG2 is downregulated in tumors including thyroid carcinoma (Mordalska et al, 2010) NDRG4 IS DOWNREGULATED IN GLIOBLASTOMArenal cancer (Ma et al, 2008) and glioblastoma (Deng et al, 2003;Shen et al, 2008;Tepel et al, 2008). NDRG2 overexpression could inhibit glioblastoma cell proliferation (Deng et al, 2003).…”

Inhibition of N-myc downstream-regulated gene 2 in prostatic carcinoma

“…5 However, some previous research has indicated that the expression of NDRG2 decreased in various carcinomas including colon cancer, thyroid cancer, glioblastoma and renal cell carcinoma. [6][7][8][9][10] The decrease suggests that NDRG2 might play an important role in the morbidity of carcinomas. Furthermore, NDRG2 has been verified to be involved in cell growth and differentiation; it may regulate myoblast proliferation and induce the differentiation of dendritic cells.…”