title: SOCS-1, a negative regulator of cytokine signaling, is frequently silenced by methylation in multiple myeloma.
abstract: The suppressor of cytokine signaling (SOCS) family of proteins has been implicated in the negative regulation of several cytokine pathways, particularly the receptor-associated tyrosine kinase/signal transducer and activator of transcription (Jak/STAT) pathways of transcriptional activation. SOCS-1 (also known as JAB and SSI-1) inhibits signaling by many cytokines. Because of the previously observed hypermethylation-associated inactivation of SOCS-1 in hepatocellular carcinoma and the critical role of interleukin-6 (IL-6) as a survival factor in multiple myeloma (MM), we examined CpG island methylation of the SOCS-1 gene in MM cell lines and primary MM samples. Aberrant SOCS-1 methylation was found in the IL-6-dependent MM cell lines U266 and XG1, which correlated with transcriptional silencing. Treatment of these cell lines with the demethylating agent 5-aza-2'-deoxycytidine (DAC) up-regulated SOCS-1 expression. Methylation-associated inactivation of SOCS-1 in hematopoietic cell lines correlated with greater sensitivity to the chemical JAK inhibitor AG490. Using methylation-specific polymerase chain reaction (MSP), we found that SOCS-1 is hypermethylated in 62.9% (23/35) of MM patient samples. In contrast, methylation analysis of malignant lymphomas of various histologies revealed SOCS-1 hypermethylation in only 3.2% (2/62), and there was no methylation of SOCS-1 in normal peripheral blood leukocytes or bone marrow cells. We conclude that SOCS-1 is frequently inactivated by hypermethylation in MM patients. Silencing of the SOCS-1 gene may impair negative regulation of the Jak/STAT pathway and therefore result in greater responsiveness to cytokines, thus supporting survival and expansion of MM cells.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Galm
authors.forename: Hirohide
authors.initials: H
authors.lastname: Yoshikawa
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.forename: Rainhardt
authors.initials: R
authors.lastname: Osieka
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
mesh_terms: D000328:Adult; D000368:Aged; D001854:Bone Marrow Cells / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism; D025461:Feedback, Physiological / Q000235:genetics; D005260:Female; D020868:Gene Silencing; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D012097:Repressor Proteins; C108944:SOCS1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators