Submitted July 13, 2006
Accepted December 18, 2006
Integrated molecular profiling of SOD2 expression in multiple myeloma
Elaine M Hurt*, Suneetha B Thomas, Benjamin Peng, and William L Farrar
Cancer Stem Cell Section, Laboratory of Cancer Prevention, Center for Cancer Research, NCI-Frederick, NIH, Frederick, MD, United States
Basic Research Program, SAIC-Frederick, NCI, Frederick, MD, United States
School of Dental Sciences, University of Melbourne, Melbourne, Australia
* Corresponding author; email: hurte{at}ncifcrf.gov.
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 as compared to normal donors. Over-expression 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.
