A Functional Proteomics Characterization of Deleted in Breast Cancer-1

Abstract

Deleted in breast cancer 1 (DBC1) has emerged as an important regulator of multiple cellular processes, ranging from gene expression to the cell cycle. As an inhibitor of members of the histone deacetylase (HDAC) family, HDAC3 and Sirtuin 1 (SIRT1), and as transcriptional cofactor for numerous nuclear hormone receptors, DBC1 has been linked to tumorigenesis. However, despite mounting interest in DBC1, relatively little is known about the range of its interacting partners, role in cancer development, and the scope of its functions. In this study, I carried out a functional proteomics characterization of DBC1 in various cell types. Using quantitative reverse-transcription polymerase chain reaction (RT-qPCR), live-cell imaging, and affinity purification coupled to tandem mass spectrometry (MS/MS), I analyzed DBC1 expression and localization, and identified a broad range of novel, highly-specific interacting partners. Using this integrated approach, I was able to expand the current understanding of the roles of DBC1 and to identify potential mechanisms by which DBC1 may participate in the regulation of RNA processing, the circadian rhythm, sister chromatid cohesion, and mitochondrial-based metabolism and apoptosis. Furthermore, I identified DBC1 interactions with components of the SWI/SNF chromatin remodeling complex and the cohesin complex, which provide compelling functional links between DBC1 and tumorigenesis. Overall, this study reveals that DBC1 has a multifaceted role in the regulation of multiple cellular processes, and could represent a therapeutic target for cancer treatment