Alterations of Genome Network Regulations and Chromatin Configurations related to Carcinogenesis

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Global gene expression networks in human cells are thought to be regulated by the chromatin configurations. Several histone and DNA modifying enzymes and possibly small noncoding RNAs are major regulators of the chromatin configurations. To clarify the alterations of the chromatin configurations in cancer cells, I studied (1) expressions of histone deacetylase genes, (2) chromatin configurations of TGFβRII promoter, and (3) small noncoding RNAs pathways in lung cancers. Reduced expression of each class II HDAC gene was significantly associated with poor prognosis and an independent predictor of poor prognosis. The group with reduced expression of class II HDACs indicated by the hierarchical clustering analysis showed also poor prognosis. We also studied chromatin configurations of TGFβRII promoter in six lung cancer cell lines. ChIP assays demonstrated three chromatin patterns for this gene silencing (Pattern I : histone H3 acetylation (H3-Ac)(±)/histone H3 lysine 4 methylation (H3K4-Me)(+)/DNA-Me(-), Pattern II; H3-Ac(-)/H3K4-Me(±)/DNA-Me(-), and Pattern III ; H3-Ac(-)/H3K4-Me(-)/DNA-Me(+)). Two members of the double-stranded RNA-specific endonuclease family, Dicer and Drosha, convert precursor forms of microRNA into their mature forms using a stepwise process. We found for the first time that Dicer expression levels were reduced in a fraction of lung cancers with a significant prognostic impact on the survival of surgically treated cases. It should be noted that multivariate COX regression analysis showed that the prognostic impact of Dicer appears to be independent of disease stage.