Down-regulation of the transcriptional mediator subunit Med1 contributes to the loss of expression of metastasis-associateddapk1in human cancers and cancer cells


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Abstract

DAPK1, a ca+2/calmodulin regulated serine/threonine kinase, is a major tumor suppressor, whose expression is lost in multiple tumor types. However, the mechanisms contributing to it are unclear. We have recently shown that CCAAT/Enhancer binding protein-β (C/EBP-β) is required for the basal and interferon γ (IFN-γ)-induced expression ofdapk1in many cell types. C/EBP-β interacts with the transcriptional Mediator, a multisubunit complex that couples enhancer bound transcription factors to the basal transcriptional machinery in an IFN-γ dependent manner for regulatingdapk1expression. Specifically, the Med1 (TRAP220/PBP/DRIP220/CRSP220) subunit associates with the enhancer bound C/EBP-β at the CRE/ATF site ofdapk1in an IFN-γ dependent manner for stimulating gene expression. Therefore, we investigated if the mechanism responsible for the loss ofdapk1expression in human cancers involves a failure to recruit C/EBP-β and/or Med1 to thedapk1promoter. We compared the relative occupancy of these factors at thedapk1promoter at CRE/ATF sites in normal and cancer cell lines. A significantly lower binding of these factors to the CRE/ATF site ofdapk1promoter occurred in human cancer cell lines than in normal cells. We show that loss of Med1 expression correlates with a corresponding loss of dapk1 expression in a number of primary human lung carcinomas. Med1 levels were significantly lower in cancer cell lines than in normal controls. Importantly, we show that restoration of Med1 induces the expression ofdapk1in these cancer cells and also attenuates their metastatic potentialin vivo.Our studies reveal a critical parameter limitingdapk1expression in cancer cell lines. © 2009 UICC

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