Targeting Histone Chaperones Retinoblastoma Binding Proteins 4 and 7 for the Treatment of Triple Negative Breast Cancer (TNBC).

[摘要] Retinoblastoma-binding proteins 4 and 7 (RBBP4/7) are ubiquitously expressed histone chaperones intimately tied to epigenetic regulation.They are subunits in several complexes that are involved in transcriptional repression including the Polycomb Repressive Complex 2 (PRC2) and the Nucleosome Remodeling and Deacetylase Complex (NuRD).Both of these complexes have been implicated in the progression of triple negative breast cancer (TNBC), the only subtype for which there is no targeted therapy.Efforts to target these complexes have demonstrated little success in TNBC.Novel strategies to inhibit these complexes are therefore required.Targeting protein-protein interactions is one of the potential routes for inhibition of epigenetic complexes.RBBP4/7 are thought to be important in recognizing histone H3 and coregulatory factors for optimal complex activity.However, the functional relevance of RBBP4/7 in TNBC is not well understood.In this report, I demonstrate that together RBBP4/7 are critical to proliferation of TNBC and maintenance of the cancer stem cell population.I further show that depletion of RBBP4 and RBBP7 is associated with a switch of gene expression from basal to luminal.The aforementioned changes were due in part to dysregulation of PRC2 and the decrease in its’ associated H3K27me3 mark.These results reveal RBBP4/7 to be a potential therapeutic target for the treatment of TNBC. As RBBP4/7 promote nucleosome association of their respective epigenetic complexes, we investigated whether interfering with the interaction of RBBP4 and histone H3 would represent a novel therapeutic approach.Examination of this binding interface on RBBP4 led to the discovery that this site is also occupied by the oncogenic transcription factor BCL11A.Treating a TNBC cell line with a BCL11A-derived peptide resulted in a 50% decrease in the activity of aldehyde dehydrogenase (ALDH), an enzyme linked to aggressiveness and poor clinical outcome in breast cancer.Together the results indicate that a decoy peptide, or a small molecule inhibitor, against RBBP4 could be an innovative approach in the treatment of TNBC.An optimized fluorescence polarization (FP) assay was developed to help discover inhibitors of this interaction and better understand its biological consequences and implications in TNBC.

[发布机构] University of Michigan

[效力级别] RBBP7

[关键词] RBBP4;RBBP7;TNBC;Biological Chemistry;Science;Chemical Biology