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The N-methyl-D-aspartate receptor type 2A is frequently methylated in human colorectal carcinoma and suppresses cell growth

Oncogene volume 27, pages 2045–2054 (2008)Cite this article

Abstract

N-methyl-D-aspartate receptors (NMDARs) are the predominant excitatory neurotransmitter receptors in the mammalian brain. We found that among the three NMDARs examined (NMDAR1, NMDAR2A, NMDAR2B), only NMDAR2A was silenced in colorectal carcinoma (CRC) cell lines at basal line and reactivated by the demethylating agent, 5-aza-2′-deoxycytidine. NMDAR2A was expressed in normal colon epithelium, while expression was hardly detectable in colon cancer tissues. Promoter methylation of NMDAR2A was confirmed by bisulfite sequencing and combined bisulfite restriction analysis in the CRC cell lines and primary tumors. Quantitative methylation-specific PCR demonstrated NMDAR2A promoter hypermethylation in 82 of 100 primary human CRC, 15 of 100 normal corresponding epithelial tissues and 1 of 11 (9%) normal colon mucosa samples obtained from patients without cancer. Moreover, forced expression of full-length NMDAR2A in CRC cell lines induced apoptosis and almost abolished the ability of the cells to form colonies in culture, while NMDAR2A knockdown increased cell growth. Thus, NMDAR2A is commonly hypermethylated in primary human CRC and possesses tumor-suppressive activity.

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Acknowledgements

Under a licensing agreement between OncoMethylome Sciences, SA and the Johns Hopkins University, Dr Sidransky is entitled to a share of royalty received by the University on sales of products described in this article. Dr Sidransky owns OncoMethylome Sciences, SA stock, which is subject to certain restrictions under University policy. Dr Sidransky is a paid consultant to OncoMethylome Sciences, SA and is a paid member of the company's Scientific Advisory Board. The term of this arrangement is being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

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Authors and Affiliations

  1. Department of Otolaryngology, Head and Neck Cancer Research Division, Johns Hopkins University, Baltimore, MD, USA

    M S Kim, X Chang, J K Nagpal, K Yamashita, S Dasgupta, G Wu, M Osada, J-H Woo, B Trink, E A Ratovitski, C Moon & D Sidransky

  2. Department of Genetic Medicine, Institute of Cell Engineering, Johns Hopkins University, Baltimore, MD, USA

    J H Baek

  3. Department of Pathology, Johns Hopkins University, Baltimore, MD, USA

    W H Westra

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  1. M S Kim
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  2. X Chang
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Correspondence to D Sidransky.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Kim, M., Chang, X., Nagpal, J. et al. The N-methyl-D-aspartate receptor type 2A is frequently methylated in human colorectal carcinoma and suppresses cell growth. Oncogene 27, 2045–2054 (2008). https://doi.org/10.1038/sj.onc.1210842

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