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Cytoglobin, the Newest Member of the Globin Family, Functions as a Tumor Suppressor Gene

¹ Hamon Center for Therapeutic Oncology Research and Departments of ² Pathology, ³ Internal Medicine, ⁴ Pharmacology, and ⁵ Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas; ⁶ Pathology, Canisius Wilhelmina Hospital, Nijmegen, the Netherlands; ⁷ Pathology and ⁸ Thoracic and Cardiovascular Surgery, University of Texas M. D. Anderson Cancer Center, Houston, Texas; and ⁹ Roy Castle Lung Cancer Research Programme, University of Liverpool, Liverpool, United Kingdom

Requests for reprints: Narayan Shivapurkar, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390. Phone: 214-648-1456; Fax: 214-648-4940; E-mail: Narayan.Shivapurkar{at}UTSouthwestern.edu.

Key Words: quantitative PCR • CYGB • methylation • tumor suppressor gene

Cytoglobin (CYGB) is a recently discovered vertebrate globin distantly related to myoglobin with unknown function. CYGB is assigned to chromosomal region 17q25, which is frequently lost in multiple malignancies. Previous studies failed to detect evidence for mutations in the CYGB gene. Recent studies provided preliminary evidence for increased methylation of the gene in lung cancer. Our study was aimed at investigating the role of CYGB as a tumor suppressor gene. By nested methylation-specific DNA sequencing analysis of lung and breast cancer cell lines and bronchial and mammary epithelial cell lines, we identified that methylation of a 110-bp CpG-rich segment of the CYGB promoter was correlated with gene silencing. We specifically targeted this sequence and developed a quantitative methylation-specific PCR assay, suitable for high-throughput analysis. We showed that the tumor specificity of CYGB methylation in discriminating patients with and without lung cancer, using biopsies and sputum samples. We further showed the tumor specificity of this assay with multiple other epithelial and hematologic malignancies. To show tumor suppressor activity of CYGB, we performed the following: (a) RNA interference–mediated knockdown of CYGB gene on colony formation in a CYGB expression–positive lung cancer cell line, resulting in increased colony formation; (b) enforced gene expression in CYGB expression–negative lung and breast cancer cell lines, reducing colony formation; and (c) identification of potential proximate targets down-stream of the CYGB genes. Our data constitute the first direct functional evidence for CYGB, the newest member of the globin family, as a tumor suppressor gene. [Cancer Res 2008;68(18):7448–56]

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