TRIM27 Positively Regulates STAT3 Activation To Promote Tumorigenesis

It has been demonstrated that IL-6-STAT3 signaling pathway plays critical roles in inflammation-associated tumorigenesis.The binding of IL-6 to its receptor IL6Ra/gp130 leads to activation of the non-receptor tyrosine kinases JAKs.Activated JAKs,in turn,mediate phosphorylation of gp130,leading to the recruitment and phosphorylation of cytosolic STAT3.The tyrosine 705 phosphorylated STAT3 dimerizes and translocates into the nucleus,where it binds to consensus sequences of promoters of the downstream target genes and regulates their transcription.Activated STAT3 induces expression of a set of genes that play crucial roles in cancer cell proliferation,survival,invasion,angiogenesis and metastasis.Despite the clear outlining of IL-6-STAT3 signaling pathway,the delicate regulatory mechanisms as well as functions in inflammation-mediated tumorigenesis remain elusive and need to be further investigated.To identify additional molecules that regulate IL-6-induced STAT3 activation,we have screened about 13000 human and mouse cDNA expression clones by STAT3-luciferase reporter assay with IL-6 as an inducer.This effort leads to the identification of the E3 ubiquitin ligase TRIM27 as a positive regulator of IL-6-induced activation of STAT3.It has been demonstrated that TRIM27 is highly expressed in many kinds of tumors and plays important roles in innate immunity and apoptosis.However,its physiological role in regulation of IL-6-STAT3 signaling is unknown.In this study,we found that overexpression of TRIM27 specifically activates STAT3 and potentiates IL-6-or OSM-induced activation of STAT3 and expression of STAT3 target genes,whereas knockdown of TRIM27 has opposite effects.In addition,IL-6-or OSM-induced transcription of STAT3 target genes is significantly inhibited in Trim27-deficient mouse hepatocytes.Consistently,overexpression of TRIM27 enhances IL-6-induced STAT3 phosphorylation,whereas knockdown of TRIM27 has opposite effects.Additionally,IL-6-induced STAT3 phosphorylation is significantly inhibited in Trim27-deficient mouse hepatocytes.Interestingly,TRIM27 regulates IL-6-STAT3 signaling independent of its E3 ligase activity.Further investigations indicate that overexpression of TRIM27 promotes interaction of JAK1 and STAT3,whereas knockdown of TRIM27 has opposite effects.Considering the IL-6-STAT3 signaling axis plays critical roles in tumorigenesis,we investigate the role of TRIM27 in tumor cell growth and tumor development.We found that overexpression of TRIM27 promotes tumorigenesis of cancer cells in vitro and in nude mice,whereas knockdown of TRIM27 has opposite effects.Furthermore,Trim27 deficiency results in resistance to AOM/DSS-induced colon cancer.These data together demonstrate that TRIM27 serves as a critical positive regulator of STAT3 by promoting complex formation of JAK1 and STAT3 to enhance STAT3 activity,and consequently promotes inflammation-associated cancer development.This study contributes to the understanding of the complicated regulatory mechanisms of STAT3 activation as well as inflammation-meditated tumorigenesis,and identifies TRIM27 as a potential target for cancer treatment.