| dc.description.abstract | In order to design patient-tailored medicine and better predict patient response totreatment and outcome, the mechanisms of altered gene expression in cancer cells mustbe understood. Recently, Single-minded 2 (SIM2) has been shown to be a breast tumorsuppressor gene that is down-regulated in approximately 72% of breast cancers, andreintroduction of SIM2 into highly metastatic cancer cells decreases their proliferativerate and their ability to grow on soft agar. SIM2 is a member of the basic helix-loophelixPer-Arnt-Sim (bHLH/PAS) family of transcription factors, which includes genesresponsible for maintenance of circadian rhythms (CLOCK and BMAL) and for sensinghypoxia (HIF-a) and environmental contaminants (AHR). Here we have shown thatSIM2 undergoes progressive epigenetic changes that correlate with loss of expressionduring breast cancer progression in a cell line model. In addition, NFB, C/EBPb andthe Notch intracellular domain (NICD) act as repressors of SIM2 transcription. Each isable to bind to the SIM2 promoter, demonstrated by chromatin immunoprecipitationassay, with the NICD acting through a novel CBF1-independent mechanism. NFB is acentral mediator of SIM2 regulation as it facilitates repression by C/EBPb and leads to deacetylation of histone 3 associated with the SIM2 promoter, contributing to epigeneticchanges observed during cancer progression. SIM2, however, also antagonizes NFBsignaling through inhibiting specific NFB target genes including the ATP-bindingcassette transporter, ABCB5, and through direct interaction with NFB. SIM2, throughthis antagonism of NFB, increases cancer cell susceptibility to antineoplastic drugs,including doxorubicin and 5-fluorouracil. | en |
