Therapeutic potential of TAF1 bromodomains for cancer treatment

Abstract

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.

Combination Targeting of the Bromodomain and Acetyltransferase Active Site of p300/CBP

“…I-CBP112 inhibition of p300 association with chromatin broadly across the genome resembles the behavior of several other bromodomain antagonists that have led to the dissociation of their cognate proteins from chromatin. [55][56][57] It is noteworthy that A-485rs acting on its own targeting the HAT "writer domain" also shows this behavior. One explanation for this is that A-485rs blocks histone acetylation and this in turn reduces the affinity of p300 for histones, via bromodomain interactions.…”

Targeting the Nuclear Receptor-Binding SET Domain Family of Histone Lysine Methyltransferases for Cancer Therapy: Recent Progress and Perspectives

“…Brennan et al 65 reported NSD1 mutation and DNA hypomethylation in patients with lung squamous cell carcinoma. Using the Cancer Genome Atlas data, Garci ́a-Carpizo et al 66 confirmed that NSD2 is highly expressed in lung cancer cells. The study showed that NSD2 is involved in the proliferation of a subset of lung cancer cells, including lung adenocarcinoma and squamous cell carcinoma via the Ras pathway.…”

The Pseudo‐Natural Product Tafbromin Selectively Targets the TAF1 Bromodomain 2

“…Importantly, whereas BAY-299 impairs cell growth most likely by a TAF1-independent mechanism, [34] Tafbromin does not affect cell viability in different cell lines (Table S3). Inactivity of Tafbromin in NIH-3T3 cells may be due to low target expression or due to modulation of a differentiation…”