Integrated molecular profiling of SOD2 expression in multiple myeloma

• Published in: Blood Vol. 109; no. 9; pp. 3953 - 3962
• Main Authors: Hurt, Elaine M., Thomas, Suneetha B., Peng, Benjamin, Farrar, William L.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.05.2007; The Americain Society of Hematology; American Society of Hematology
• Series: Neoplasia
• Subjects: 2-Methoxyestradiol; Animals; Apoptosis - drug effects; Apoptosis - genetics; Biological and medical sciences; Cell Line, Tumor; DNA Damage - drug effects; DNA Damage - genetics; Estradiol - analogs & derivatives; Estradiol - pharmacology; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - genetics; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Hematologic and hematopoietic diseases; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Multiple Myeloma - enzymology; Multiple Myeloma - genetics; Neoplasia; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Proteomics; Reactive Oxygen Species; Signal Transduction - drug effects; Signal Transduction - genetics; Superoxide Dismutase - biosynthesis; Superoxide Dismutase - genetics; Tubulin Modulators - pharmacology; Immunopathology; Immunoglobulinopathy; Hematology; Lymphoproliferative syndrome; Malignant hemopathy; Myeloma; Gene expression profile
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2006-07-035162

Reactive oxygen species are known to be involved in several cellular processes, including cell signaling. SOD2 is a key enzyme in the conversion of reactive oxygen species and has been implicated in a host of disease states, including cancer. Using an integrated, whole-cell approach encompassing epigenetics, genomics, and proteomics, we have defined the role of SOD2 in multiple myeloma. We show that the SOD2 promoter is methylated in several cell lines and there is a correlative decrease in expression. Furthermore, myeloma patient samples have decreased SOD2 expression compared with healthy donors. Overexpression of SOD2 results in decreased proliferation and altered sensitivity to 2-methoxyestradiol–induced DNA damage and apoptosis. Genomic profiling revealed regulation of 65 genes, including genes involved in tumorigenesis, and proteomic analysis identified activation of the JAK/STAT pathway. Analysis of nearly 400 activated transcription factors identified 31 transcription factors with altered DNA binding activity, including XBP1, NFAT, forkhead, and GAS binding sites. Integration of data from our gestalt molecular analysis has defined a role for SOD2 in cellular proliferation, JAK/STAT signaling, and regulation of several transcription factors.