Fig. 5

Pharmacological targeting SE-driven transcriptional program in cancer. Inhibition of histone deacetylase enzymes (HDACs) with romidepsin or virinostat disrupts acetylation marks levels, impeding the interactions between SEs and promoters. Suppression of the enzymatic activity of histone acetyltransferases CBP/p300 with ICG-001 or CBP30 perturbs SE formation. Treatment with coactivator-associated arginine methyltransferase 1 (CARM1) inhibitor TP-064 hampers the methylation of BAF155, impairing the recruitment of BRD4 and the formation of SEs. Inhibition of the H3K27 demethylase KDM6 with GSK-J4 leads to widespread enhancer reorganization, particularly affecting stemness genes regulated by SEs. JQ1 and OTX015 specifically target BRD4, leading to a reduction in the recruitment of Mediator, BRD4, and RNA Pol II at SE sites. Inhibitors targeting CDKs, upregulate or downregulate the transcription of SE-associated genes through affecting phosphorylation C-terminal domain (CTD) of RNA Pol II. Proteolysis-targeting chimeras (PROTACs) can selectively hijack BRD4, CDKs and TFs into the ubiquitin-proteasome system to elicit its degradation, resulting to interruption of SE-driven transcriptional program. CRISPR/Cas9-mediated genetic perturbation can directly targeting individual components within SEs