IL-6-induced DNMT1 activity mediates SOCS3 promoter hypermethylation in ulcerative colitis-related colorectal cancer.
Ulcerative colitis (UC) is associated with a high risk of developing colorectal cancer (CRC). The mechanisms by which chronic inflammatory responses in the colon may promote CRC remain only partially understood, but may involve reduced negative regulation of interleukin (IL)-6 signaling towards signal transducer and activator of transcription 3 activation through the loss of SOCS3 expression, unleashing the full carcinogenic potential of this transcription factor. Thus, we analyzed SOCS3 expression in the colon of healthy controls, as well as in a cohort of UC patients with varying degrees of dysplasia. We observe that the loss of epithelial SOCS3 expression delimits the areas subject to dysplasia in UC, suggesting an important tumour-suppressive role of SOCS3 downregulation, early in the transformation process. Importantly, methylation of the SOCS3 promotor appears to constitute an important regulatory mechanism for colonic SOCS3 expression as SOCS3 methylation status in CRC cells correlates with a disability to upregulate SOCS3 upon IL-6 stimulation, whereas forced demethylation using 5-aza-2'-deoxycytidine restores SOCS3 expression and inhibits IL-6-induced p-signal transducer and activator of transcription 3 activation and proliferation. Expression of the DNA methyltransferase gene DMNT1 is prominent in dysplastic cells and correlates with low or absent SOCS3 expression. Thus, induction of DNMT1 expression in the chronically inflamed colon may release IL-6 signaling towards signal transducer and activator of transcription 3 from inhibition through SOCS3 increasing the propensity to malignant transformation. Hence, DNMT1 emerges as a rational target in preventive strategies aimed at counteracting UC-CRC.
Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, Netherlands. yili1101@hotmail.com
Yi
Y
Li
Jasper
J
Deuring
Maikel P
MP
Peppelenbosch
Ernst J
EJ
Kuipers
Colin
C
de Haar
C Janneke
CJ
van der Woude
D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D003093:Colitis, Ulcerative / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*
D015850:Interleukin-6; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human