Molecular mechanisms of associations between abnormal differentiation and altered regulations of gene expressions.

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The proneural basic-helix-loop-helix protein achaete-scute homologue 1(ASH1) is expressed in a very limited spectrum in a lineage-specific manner, including normal pulmonary neuroendocrine cells and lung cancer cells with neuroendocrine features. Our previous results indicated that ASH1 may play a crucial role in the growth and survival of lung cancers with neuroendocrine features. In the present study, we report for the first time that ASH1 functions as a dual transcription factor by activating neuroendocrine differentiation markers and also repressing putative tumor suppressors. This protein was found to inactivate DKK1 and DKK3, negative regulators of Wnt/β-catenin signaling, E-cadherin, and integrinβ1 through ASH 1-mediated deacetylation and repressive trimethylation of lysine 27(H3K27me3) of histone H3 in the promoter regions of DKK1 and E-cadherin. Our results provide important clues for a better understanding of the molecular and cellular biological roles of ASH1 in the process … More of carcinogenesis of lung cancers with neuroendocrine features and warrant future investigations to shed light on the lineage-specific dependency of this transcription factor with dual functions.We previously reported the amplification and overexpression of the miR-17-92 microRNAs(miRNA) cluster at 13q31.3 in lung cancers. In the present study, we show that inhibition of miR-17-5p and miR-20a with antisense oligonucleotides can induce apoptosis selectively in lung cancer cells overexpressing miR-17-92, suggesting the possibility of 'OncomiR addiction' to expression of these miRNAs in a subset of lung cancers. During the course of this study, we also found that enforced expression of a genomic region, termed C2, residing 3' to miR-17-92 in the intron 3 of C13orf25 led to marked growth inhibition in association with double stranded RNA-dependent protein kinase activation. Taken together, the present findings contribute towards better understanding of the oncogenic roles of miR-17-92, which might ultimately lead to the future translation into clinical applications. Less