Functional studies of the chromosome 3p21.3 candidate tumor suppressor gene BLU/ZMYND10 in nasopharyngeal carcinoma†
Wing Lung Yau
Department of Biology and Center for Cancer Research, The Hong Kong University of Science and Technology, Hong Kong (SAR), China
Search for more papers by this authorHong Lok Lung
Department of Biology and Center for Cancer Research, The Hong Kong University of Science and Technology, Hong Kong (SAR), China
Search for more papers by this authorEugene R. Zabarovsky
Microbiology and Tumor Biology Center and Center for Genomics and Bioinformatics, Karolinska Institute, Stockholm, Sweden
Search for more papers by this authorMichael I. Lerman
Laboratory of Immunobiology, Center for Cancer Research, National Cancer Institute, Frederick, MD
Search for more papers by this authorJonathan Shun-tong Sham
Department of Clinical Oncology, University of Hong Kong, Pokfulam, Hong Kong (SAR), China
Search for more papers by this authorDaniel Tsin-tien Chua
Department of Clinical Oncology, University of Hong Kong, Pokfulam, Hong Kong (SAR), China
Search for more papers by this authorSai Wah Tsao
Department of Anatomy, University of Hong Kong, Pokfulam, Hong Kong (SAR), China
Search for more papers by this authorEric J. Stanbridge
Department of Microbiology and Molecular Genetics, University of California, Irvine, CA
Search for more papers by this authorCorresponding Author
Maria Li Lung
Department of Biology and Center for Cancer Research, The Hong Kong University of Science and Technology, Hong Kong (SAR), China
Fax: +852-2358-1559.
Department of Biology and Center for Cancer Research, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong (SAR), ChinaSearch for more papers by this authorWing Lung Yau
Department of Biology and Center for Cancer Research, The Hong Kong University of Science and Technology, Hong Kong (SAR), China
Search for more papers by this authorHong Lok Lung
Department of Biology and Center for Cancer Research, The Hong Kong University of Science and Technology, Hong Kong (SAR), China
Search for more papers by this authorEugene R. Zabarovsky
Microbiology and Tumor Biology Center and Center for Genomics and Bioinformatics, Karolinska Institute, Stockholm, Sweden
Search for more papers by this authorMichael I. Lerman
Laboratory of Immunobiology, Center for Cancer Research, National Cancer Institute, Frederick, MD
Search for more papers by this authorJonathan Shun-tong Sham
Department of Clinical Oncology, University of Hong Kong, Pokfulam, Hong Kong (SAR), China
Search for more papers by this authorDaniel Tsin-tien Chua
Department of Clinical Oncology, University of Hong Kong, Pokfulam, Hong Kong (SAR), China
Search for more papers by this authorSai Wah Tsao
Department of Anatomy, University of Hong Kong, Pokfulam, Hong Kong (SAR), China
Search for more papers by this authorEric J. Stanbridge
Department of Microbiology and Molecular Genetics, University of California, Irvine, CA
Search for more papers by this authorCorresponding Author
Maria Li Lung
Department of Biology and Center for Cancer Research, The Hong Kong University of Science and Technology, Hong Kong (SAR), China
Fax: +852-2358-1559.
Department of Biology and Center for Cancer Research, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong (SAR), ChinaSearch for more papers by this authorThis article is a US Government work and, as such, is in the public domain in the United States of America.
Abstract
Chromosome 3p plays an important role in tumorigenesis in many cancers, including nasopharyngeal carcinoma (NPC). We have previously shown chromosome 3p can suppress tumor growth in vivo by using the monochromosome transfer approach, which indicated the chromosome 3p21.3 region was critical for tumor suppression. BLU/ZMYND10 is one of the candidate tumor suppressor genes mapping in the 3p21.3 critical region and is a candidate TSG for NPC. By quantitative RT-PCR, it is frequently downregulated in NPC cell lines (83%) and NPC biopsies (80%). However, no functional studies have yet verified the functional role of BLU/ZMYND10 as a tumor suppressor gene. In the current study, a gene inactivation test (GIT) utilizing a tetracycline regulation system was used to study the functional role of BLU/ZMYND10. When BLU/ZMYND10 is expressed in the absence of doxycycline, the stable transfectants were able to induce tumor suppression in nude mice. In contrast, downregulation of BLU/ZMYND10 in these tumor suppressive clones by doxycycline treatment restored the tumor formation ability. This study provides the first significant evidence to demonstrate BLU/ZMYND10 can functionally suppress tumor formation in vivo and is, therefore, likely to be one of the candidate tumor suppressor genes involved in NPC. Published 2006 Wiley-Liss, Inc.
References
- 1 Lo KW, Huang DP. Genetic and epigenetic changes in nasopharyngeal carcinoma. Semin Cancer Biol 2002; 12: 451–62. Review.
- 2 Shao JY, Huang XM, Yu XJ, Huang LX, Wu QL, Xia JC, Wang HY, Feng QS, Ren ZF, Ernberg I, Hu LF, Zeng YX. Loss of heterozygosity and its correlation with clinical outcome and Epstein-Barr virus infection in nasopharyngeal carcinoma. Anticancer Res 2001; 21: 3021–9.
- 3 Li X, Wang E, Zhao YD, Ren JQ, Jin P, Yao KT, Marincola FM. Chromosomal imbalances in nasopharyngeal carcinoma: a meta-analysis of comparative genomic hybridization results. J Translational Med 2006; 4: 4.
- 4 Cheng Y, Poulos NE, Lung ML, Hampton G, Ou B, Lerman MI, Stanbridge EJ. Functional evidence for a nasopharyngeal carcinoma tumor suppressor gene that maps at chromosome 3p21.3. Proc Natl Acad Sci USA 1998; 95: 3042–7.
- 5
Cheng Y,
Stanbridge EJ,
Kong H,
Bengtsson U,
Lerman MI,
Lung ML.
A functional investigation of tumor suppressor gene activities in a nasopharyngeal carcinoma cell line HONE1 using a monochromosome transfer approach.
Genes Chromosomes Cancer
2000;
28:
82–91.
10.1002/(SICI)1098-2264(200005)28:1<82::AID-GCC10>3.0.CO;2-8 CAS PubMed Web of Science® Google Scholar
- 6 Cheng Y, Chakrabarti R, Garcia-Barcelo M, Ha TJ, Srivatsan ES, Stanbridge EJ, Lung ML. Mapping of nasopharyngeal carcinoma tumor-suppressive activity to a 1.8-megabase region of chromosome band 11q13. Genes Chromosomes Cancer 2002; 34: 97–103.
- 7 Lung HL, Cheng Y, Kumaran MK, Liu ET, Murakami Y, Chan CY, Yau WL, Ko JM, Stanbridge EJ, Lung ML. Fine mapping of the 11q22-23 tumor suppressive region and involvement of TSLC1 in nasopharyngeal carcinoma. Int J Cancer 2004; 112: 628–35.
- 8 Cheng Y, Ko JM, Lung HL, Lo PH, Stanbridge EJ, Lung ML. Monochromosome transfer provides functional evidence for growth-suppressive genes on chromosome 14 in nasopharyngeal carcinoma. Genes Chromosomes Cancer 2003; 37: 359–68.
- 9 Cheng Y, Lung HL, Wong PS, Hao DC, Man CS, Stanbridge EJ, Lung ML. Chromosome 13q12 region critical for the viability and growth of nasopharyngeal carcinoma hybrids. Int J Cancer 2004; 109: 357–62.
- 10 Lerman MI, Minna JD. The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. The international lung cancer chromosome 3p21.3 tumor suppressor gene consortium. Cancer Res 2000; 60: 6116–33.
- 11 Chow LS, Lam CW, Chan SY, Tsao SW, To KF, Tong SF, Hung WK, Dammann R, Huang DP, Lo KW. Identification of RASSF1A modulated genes in nasopharyngeal carcinoma. Oncogene 2006; 25: 310–6.
- 12 Qiu GH, Tan LK, Loh KS, Lim CY, Srivastava G, Tsai ST, Tsao SW, Tao Q. 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 2004; 23: 4793–806.
- 13 Ito M, Ito G, Kondo M, Uchiyama M, Fukui T, Mori S, Yoshioka H, Ueda Y, Shimokata K, Sekido Y. Frequent inactivation of RASSF1A, BLU, and SEMA3B on 3p21.3 by promoter hypermethylation and allele loss in non-small cell lung cancer. Cancer Lett 2005; 225: 131–9.
- 14 Agathanggelou A, Dallol A, Zochbauer-Muller S, Morrissey C, Honorio S, Hesson L, Martinsson T, Fong KM, Kuo MJ, Yuen PW, Maher ER, Minna JD, Latif F. Epigenetic inactivation of the candidate 3p21.3 suppressor gene BLU in human cancers. Oncogene 2003; 22: 1580–8.
- 15 Lo PHY, Leung ACC, Xiong W, Law S, Duh FM, Lerman MI, Stanbridge EJ, Lung ML. Expression of candidate chromosome 3p21.3 tumor suppressor genes and down-regulation of BLU in some esophageal squamous cell carcinomas. Cancer Lett 2006; 234: 184–92.
- 16 Liu XQ, Chen HK, Zhang XS, Pan ZG, Li A, Feng QS, Long QX, Wang XZ, Zeng YX. Alterations of BLU, a candidate tumor suppressor gene on chromosome 3p21.3, in human nasopharyngeal carcinoma. Int J Cancer 2003; 106: 60–5.
- 17 Tsao SW, Wang X, Liu Y, Cheung YC, Feng H, Zheng Z, Wong N, Yuen PW, Lo AK, Wong YC, Huang DP. Establishment of two immortalized nasopharyngeal epithelial cell lines using SV40 large T and HPV16E6/E7 viral oncogenes. Biochim Biophys Acta 2002; 1590: 150–8.
- 18 Protopopov AI, Li J, Winberg G, Gizatullin RZ, Kashuba VI, Klein G, Zabarovsky ER. Human cell lines engineered for tetracycline-regulated expression of tumor suppressor candidate genes from a frequently affected chromosomal region, 3p21. J Gene Med 2002; 4: 397–406.
- 19 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402–8.
- 20 Lung HL, Bangarusamy DK, Xie D, Cheung AK, Cheng Y, Kumaran MK, Miller L, Liu ET, Guan XY, Sham JS, Fang Y, Li L et al. THY1 is a candidate tumour suppressor gene with decreased expression in metastatic nasopharyngeal carcinoma. Oncogene 2005; 24: 6525–32.
- 21
Chen YJ,
Ko JY,
Chen PJ,
Shu CH,
Hsu MT,
Tsai SF,
Lin CH.
Chromosomal aberrations in nasopharyngeal carcinoma analyzed by comparative genomic hybridization.
Genes Chromosomes Cancer
1999;
25:
169–75.
10.1002/(SICI)1098-2264(199906)25:2<169::AID-GCC13>3.0.CO;2-I CAS PubMed Web of Science® Google Scholar
- 22 Chmara M, Wozniak A, Ochman K, Kobierska G, Dziadziuszko R, Sosinska-Mielcarek K, Jassem E, Skokowski J, Jassem J, Limon J. Loss of heterozygosity at chromosomes 3p and 17p in primary non-small cell lung cancer. Anticancer Res 2004; 24: 4259–63.
- 23 Alimov A, Kost-Alimova M, Liu J, Li C, Bergerheim U, Imreh S, Klein G, Zabarovsky ER. Combined LOH/CGH analysis proves the existence of interstitial 3p deletions in renal cell carcinoma. Oncogene 2000; 19: 1392–9.
- 24 Ko JM, Wong CP, Tang CM, Lau KW, Lung ML. Frequent loss of heterozygosity on multiple chromosomes in Chinese esophageal squamous cell carcinomas. Cancer Lett 2001; 170: 131–8.
- 25 Chan AS, To KF, Lo KW, Mak KF, Pak W, Chiu B, Tse GM, Ding M, Li X, Lee JC, Huang DP. High frequency of chromosome 3p deletion in histologically normal nasopharyngeal epithelia from southern Chinese. Cancer Res 2000; 60: 5365–70.
- 26 Huang DP, Lo KW, Choi PH, Ng AY, Tsao SY, Yiu GK, Lee JC. Loss of heterozygosity on the short arm of chromosome 3 in nasopharyngeal carcinoma. Cancer Genet Cytogenet 1991; 54: 91–9.
- 27 Chow LS, Lo KW, Kwong J, To KF, Tsang KS, Lam CW, Dammann R, Huang DP. RASSF1A is a target tumor suppressor from 3p21.3 in nasopharyngeal carcinoma. Int J Cancer 2004; 109: 839–47.
- 28 Zhou L, Jiang W, Ren C, Yin Z, Feng X, Liu W, Tao Q, Yao K. Frequent hypermethylation of RASSF1A and TSLC1, and high viral load of Epstein-Barr Virus DNA in nasopharyngeal carcinoma and matched tumor-adjacent tissues. Neoplasia 2005; 7: 809–15.
- 29 Li J, Wang F, Protopopov A, Malyukova A, Kashuba V, Minna JD, Lerman MI, Klein G, Zabarovsky E. Inactivation of RASSF1C during in vivo tumor growth identifies it as a tumor suppressor gene. Oncogene 2004; 23: 5941–9.
- 30 Hessen L, Bieche I, Krex D, Criniere E, Hoang-Xuan K, Maher ER, Latif F. Frequent epigenetic inactivation of RASSF1A and BLU genes located within the critical 3p21.3 region in gliomas. Oncogene 2004; 23: 2408–19.
- 31 Wan J, Zhang W, Wu L, Bai T, Zhang M, Lo KW, Chui YL, Cui Y, Tao Q, Yamamoto M, Akira S, Wu Z. BS69, a specific adaptor in the latent membrane protein 1-mediated c-Jun N-terminal kinase pathway. Mol Cell Biol 2006; 26: 448–56.