Abstract 4026: Id4 acts as a tumor suppressor by regulating c-Myc and MDM2 in prostate cancer

Abstract

Abstract PURPOSE: Id proteins (Id1, Id2, Id3, and Id4) function as dominant negative regulators of basic helix loop helix transcription factor family. They share the conserved HLH domain but lack the DNA binding basic domain. This domain configuration allows the Id proteins to dimerize with bHLH proteins. The Id-bHLH dimer therefore fails to bind the E box consensus sequence and activate transcription. In general Id1 and Id3 promote proliferation and inhibit differentiation and thus their expression is generally high in many cancers. The function of Id4 appears to be unique as compared to Id1-Id3. Recent studies have demonstrated that Id4 is epigenetically silenced in many cancers suggesting that Id4 may in fact act as a tumor suppressor. The present study was carried out to determine the molecular mechanism by which Id4 acts as a tumor suppressor in prostate cancer. DESIGN METHODS: Initial studies were carried out on DU145 cells in which Id4 is epigenetically silenced. Over-expression of Id4 decreased proliferation and promoted epithelial like morphology in DU145 cells. A proteomics based approach suggested that MDM2 is a potential downstream target of Id4. The upstream regulators and downstream targets of MDM2 were then evaluated to understand the mechanism and functional significance of Id4-MDM2 cross talk. RESULTS: A combination of expression and immuno-localization studies demonstrated that c-Myc and p14ARF, the upstream regulators of MDM2 expression are down-regulated in the presence of Id4. Id4 also significantly up-regulated the expression and nuclear localization of CDKNIs p21and p27. Unexpectedly, the expression of p53 a known target of MDM2 was decreased both at the transcript and protein level. CONCLUSIONS: Although MDM2 was discovered as a potential downstream target, our pathway analysis suggests that c-Myc could also be a downstream target of Id4. The de-repression of CDKNI appears to be c-Myc dependent but p53 independent primarily because in DU145 cells, p53 is mutated. Alternatively, decreased MDM2 could promote p21 stability resulting in increased nuclear localization and expression. Taken together our data support the role of Id4 as a potential tumor suppressor that is unique and opposite to the oncogenic properties of other HLH members Id1, Id2 and Id3. Supported by: NIH/NCI R01CA128914 and NIH/NCRR/RCMI G12RR03062. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4026. doi:10.1158/1538-7445.AM2011-4026