BRD8 is a potential chemosensitizing target for spindle poisons in colorectal cancer therapy

Survival rate of metastatic colorectal cancers is less than 5%. A major reason is that those cancers respond poorly to chemotherapy drugs. However, factors contributing to chemoresistance in colorectal cancers are barely known, thus isolation of factors involved is the critical first step for mechanistic understanding and therapy improvement. With expression cloning, we isolated human BRD8 (bromodomain 8) as an influential factor for spindle poison sensitivity. BRD8 is an accessory subunit of human NuA4-HAT (histone acetyl transferase) complex (also known as TRRAP/TIP60 complex), but its role in cancer and drug resistance is unknown. Here, we report that BRD8 is involved in cellular survival and in sensitivity to spindle poisons and proteasome inhibitor in aggressive colorectal cancers. BRD8 protein expression level is several-fold higher in human metastatic colorectal cancer cell lines (DLD-1, HCA-7 and HCT-116) than in other cell lines tested. Normal-appearing rat colonic mucosa and azoxymethane (AOM)-induced colorectal adenocarcinoma tissue expressed a barely detectable amount of BRD8 protein, but aggressive colon tumors induced with AOM and dextran sodium sulfate expressed BRD8 at a significantly higher level, suggesting that BRD8 expression is associated with tumor progression toward advanced stages and may aid to gain growth advantage. Supporting the notion, siRNA-mediated knockdown of BRD8 induced cell death or growth delay in colorectal cancer cell lines, and surviving BRD8-knockdown cells were particularly sensitive to spindle poisons and a proteasome inhibitor MG132. Conversely, at least one isoform of BRD8 gave growth advantage and resistance to taxol when stably overexpressed in HeLa cells. Targeting BRD8 would improve therapy outcome against aggressive/metastatic colorectal cancers.