RT Journal Article
SR Electronic
T1 Therapeutic potential of TAF1 bromodomains for cancer treatment
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 394254
DO 10.1101/394254
A1 Veronica Garcia-Carpizo
A1 Sergio Ruiz-Llorente
A1 Jacinto Sarmentero
A1 Maria J. Barrero
YR 2018
UL http://biorxiv.org/content/early/2018/08/17/394254.abstract
AB The discovery of the antiproliferative effects of BRD4 bromodomain inhibitors prompted us to investigate additional bromodomains that might be involved in supporting cellular proliferation. TAF1 is a general transcription factor with two bromodomains that is likely to play important roles in cell viability by supporting transcription. Our work shows that knock down of TAF1 caused antiproliferative effects in several cancer cell lines. Using CRISPR-Cas9 editing techniques we demonstrate that the bromodomains of TAF1 are essential to maintain proliferation of K562 and H322 cells. BAY-299, the best TAF1 bromodomain inhibitor developed so far, also showed antiproliferative effects. BAY-299 caused discrete transcriptional changes that were likely on target but did not correlate with strong effects in cell cycle distribution suggesting that these effects might be, at least in part, mediated by another target. Compared to the TAF1 knock down, BAY-299 specifically downregulated the expression of genes with high levels of TAF1 and histone acetylation at their promoters, suggesting that targeting the bromodomains has distinct transcriptional effects than targeting the whole protein. This might help to provide a therapeutic window to target specifically cancer cells with high levels of histone acetylation at proliferation-related genes.