DIVERSITY OF CANCER CELLS CAUSED BY CYTOSINE METHYLATION IN NON-CPG ISLAND

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Although global methylation at CpG islands leads to gene silencing, specific methylation at non-CpG islands would play a crucial epigenetic role in the versatility and plasticity of gene expression during cancer progression. We demonstrated the negative cis-acting AP-1-like sequence TGAGCGA in the 5'-untranslated region of the TrkA gene. Steady-state TrkA expression correlated positively with the accumulation of methylated CpG around the AP-1-like site. By EMSA, the AP-1-like site was bound mainly by c-Jun homodimers; the binding was blocked by Sss I-induced methylation. Consequently, activation of TrkA gene expression by methylation was caused by the direct interference of c-Jun binding to the negatively regulating AP-1-like site. Furthermore, methylated CpG around the AP-1-like site was accumulated with increased TrkA expression in cases of advanced pancreatic cancer with extensive perineural invasion.A rare case of desmoid-type fibromatosis with metaplastic ossification in the chest wall is analyzed. Accumulation of beta-catenin associated with a somatic activating mutation in codon 41 was demonstrated. Bisulfite mapping using microdissected samples showed that BMP and activin membrane-bound inhibitor (BAMBI) expression was specifically downregulated at the ossifying focus due to hypermethylation of its gene promoter. Because both BMP and classical Wnt/beta-catenin/LEF1 signaling cooperatively and mutually induce differentiation of mesenchymal cells into osteoblastic cells and promote bone formation, the epigenetic event leading to the enhanced responsiveness to BMP signaling may play a crucial role in the formation of metaplastic bone.We have presented our data at various international as well as domestic meetings, and published scientific papers for academic journals.