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  • Oncogenomics
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The candidate tumor suppressor gene BLU, located at the commonly deleted region 3p21.3, is an E2F-regulated, stress-responsive gene and inactivated by both epigenetic and genetic mechanisms in nasopharyngeal carcinoma

Oncogene volume 23, pages 4793–4806 (2004)Cite this article

Abstract

Loss of heterozygosity at 3p21 is common in various cancers including nasopharyngeal carcinoma (NPC). BLU is one of the candidate tumor suppressor genes (TSGs) in this region. Ectopic expression of BLU results in the inhibition of colony formation of cancer cells, suggesting that BLU is a tumor suppressor. We have identified a functional BLU promoter and found that it can be activated by environmental stresses such as heat shock, and is regulated by E2F. The promoter and first exon are located within a CpG island. BLU is highly expressed in testis and normal upper respiratory tract tissues including nasopharynx. However, in all seven NPC cell lines examined, BLU expression was downregulated and inversely correlated with promoter hypermethylation. Biallelic epigenetic inactivation of BLU was also observed in three cell lines. Hypermethylation was further detected in 19/29 (66%) of primary NPC tumors, but not in normal nasopharyngeal tissues. Treatment of NPC cell lines with 5-aza-2′-deoxycytidine activated BLU expression along with promoter demethylation. Although hypermethylation of RASSF1A, another TSG located immediately downstream of BLU, was detected in 20/27 (74%) of NPC tumors, no correlation between the hypermethylation of these two TSGs was observed (P=0.6334). In addition to methylation, homozygous deletion of BLU was found in 7/29 (24%) of tumors. Therefore, BLU is a stress-responsive gene, being disrupted in 83% (24/29) of NPC tumors by either epigenetic or genetic mechanisms. Our data are consistent with the interpretation that BLU is a TSG for NPC.

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Acknowledgements

We thank Drs Dolly Huang, Kaitai Yao, Guiyuan Li, Ya Cao, Huaizhong Hu, Goh Boon Cher, Lee Soo Chin, and Paul Murray for cell lines and samples, and Tim Huang for valuable discussion on methylation spreading. This project was supported by an A*STAR research grant to Johns Hopkins Singapore (Q.T. and R.A.). We thank Drs Keith Robertson and Richard Ambinder for critical reading of the paper.

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Authors and Affiliations

  1. Division of Johns Hopkins in Singapore, Cancer Epigenetics/Tumor Virology Laboratory, Singapore

    Guo-Hua Qiu, Chai Yen Lim & Qian Tao

  2. Department of Otolaryngology, National University of Singapore, Singapore

    Luke KS Tan & Kwok Seng Loh

  3. Department of Pathology, University of Hong Kong, China

    Gopesh Srivastava

  4. Department of Otolaryngology, National Cheng Kung University, Taiwan, China

    Sen-Tien Tsai

  5. Department of Anatomy, University of Hong Kong, China

    Sai Wah Tsao

  6. Sydney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, USA

    Qian Tao

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  1. Guo-Hua Qiu
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Note added in proof

During the revision of this manuscript, two groups published their work of the detection of BLU methylation in four NPC cell lines (Agathanggelou et al. (2003). Oncogene, 22, 1580–1588) and 74% of primary tumors (Liu et al. (2003). Int. J. Cancer, 106, 60–65).

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Qiu, GH., Tan, L., Loh, K. et al. The candidate tumor suppressor gene BLU, located at the commonly deleted region 3p21.3, is an E2F-regulated, stress-responsive gene and inactivated by both epigenetic and genetic mechanisms in nasopharyngeal carcinoma. Oncogene 23, 4793–4806 (2004). https://doi.org/10.1038/sj.onc.1207632

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