Suppressor of Cytokine Signaling (SOCS) Genes Are Silenced by DNA Hypermethylation and Histone Deacetylation and Regulate Response to Radiotherapy in Cervical Cancer Cells

Abstract

Suppressor of cytokine signaling (SOCS) family is an important negative regulator of cytokine signaling and deregulation of SOCS has been involved in many types of cancer. All cervical cancer cell lines tested showed lower expression of SOCS1, SOCS3, and SOCS5 than normal tissue or cell lines. The immunohistochemistry result for SOCS proteins in human cervical tissue also confirmed that normal tissue expressed higher level of SOCS proteins than neighboring tumor. Similar to the regulation of SOCS in other types of cancer, DNA methylation contributed to SOCS1 downregulation in CaSki, ME-180, and HeLa cells. However, the expression of SOCS3 or SOCS5 was not recovered by the inhibition of DNA methylation. Histone deacetylation may be another regulatory mechanism involved in SOCS1 and SOCS3 expression, however, SOCS5 expression was neither affected by DNA methylation nor histone deacetylation. Ectopic expression of SOCS1 or SOCS3 conferred radioresistance to HeLa cells, which implied SOCS signaling regulates the response to radiation in cervical cancer. In this study, we have shown that SOCS expression repressed by, in part, epigenetically and altered SOCS1 and SOCS3 expression could contribute to the radiosensitive phenotype in cervical cancer.

Epigenetic silencing of SOCS5 potentiates JAK‐STAT signaling and progression of T‐cell acute lymphoblastic leukemia

“…Although mutations in the SOCS family genes are very rare, aberrant SOCS signaling has been linked to the epigenetic deregulation of their expression . For instance, reduced levels of SOCS5 mRNA and its promoter hypermethylation were reported in hepatocellular carcinoma, cervical cancer, and thyroid tumors . In this study, we dissected the mechanism of epigenetic deregulation of SOCS5 expression in T‐ALL through aberrant DNA methylation.…”

“…DNMT3A was identified to negatively regulate the SOCS5 expression levels in T‐ALL cells. Histone acetylation has also been implicated in the epigenetic regulation of the SOCS family genes in solid tumors . In addition, early studies identified the CpG binding protein, MeCP2 as a transcriptional silencer .…”

“…The results were consistent with our knockdown studies, in which SOCS5 inactivation accelerated cell growth and cell cycle progression in T‐ALL cells. SOCS5 downregulation and its tumor suppressive role were reported in cervical and thyroid cancers . However, in chronic lymphocytic leukemia patients, increased SOCS5 expression governed the defective function of dendritic cells .…”

“…The SOCS family of cytokine‐inducible negative regulators of JAK‐STAT and other signaling pathways includes 8 structurally related family members, SOCS1‐7 and CIS, all of which contain a central Src‐homology 2 domain and a conserved C‐terminal domain termed the SOCS box . There is growing evidence implicating SOCS family members in a range of inflammatory diseases and tumors, including hepatocellular carcinoma, colorectal, cervical, and breast cancer . Downregulation of SOCS genes was reported in solid tumors with an unfavorable prognosis and hematological malignancies, including AML, and myeloproliferative disorders …”

“…There is growing evidence implicating SOCS family members in a range of inflammatory diseases and tumors, including hepatocellular carcinoma, colorectal, cervical, and breast cancer . Downregulation of SOCS genes was reported in solid tumors with an unfavorable prognosis and hematological malignancies, including AML, and myeloproliferative disorders …”