Chemical modulators for epigenome reader domains as emerging epigenetic therapies for cancer and inflammation

Abstract

Site-specific lysine acetylation and methylation on histones are critical post-translational modifications (PTMs) that govern ordered gene transcription in chromatin. Mis-regulation of these histone PTM-mediated processes has been shown to be associated with human diseases. Since the 2010 landmark reports of small molecules (+)-JQ1 and I-BET762 that target the acetyl-lysine ‘reader’ Bromodomain and Extra Terminal domain (BET) proteins, there have been relentless efforts to develop epigenetic therapy with small molecules to modulate molecular interactions of epigenome reader domain proteins with PTMs. In addition to BET, the other emerging targets include non-BET acetyl- and methyl-lysine reader domains. This review covers the key chemical modulators of the aforementioned epigenome reader proteins.

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

“…The mammalian bromodomain and extra-terminal domain (BET) family, comprising BRD2, BRD3, BRD4, and BRDT, is involved in transcriptional regulation of cancer-related genes and has been recognized as a therapeutic target in many cancer types, such as NUT midline carcinoma (NMC) [4] and acute myeloid leukemia (AML) [5]. JQ1, an inhibitor of BET proteins that binds the acetyllysine (Kac)-binding pocket of bromodomain [4], has been shown to selectively suppress the expression of tumor-promoting genes in cancer cells and emerges as a promising anti-cancer therapeutic drug [3,4,6–10]. Since studies on BET inhibition mechanisms have mostly focused on the correlation between BRD4 genomic occupancy and JQ1-induced transcriptional changes [6,11], little is known on how BRD2 and hyperacetylated histone H4, as the direct chromatin target of BET proteins, engage in the cancer-related pathways.…”

“…The BET family shares a C-terminal extra-terminal domain and two tandem bromodomains, BD1 and BD2, that primarily bind to multi-acetylated histone H4 tail at K5, K8, K12, and K16 in vitro , but not to the monoacetylated histone H3/H4 peptides, including that of acetylated H3 K27 (H3K27ac) [9,10,12,13]. Since acetylation of histone H4 in the nucleus is proposed to occur at K16 first, then at K12, K8, and K5 [14], the simultaneous acetylation of K5 and K8 indicates a typical state of histone H4 hyperacetylation [14].…”

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

“…Mammalian bromodomain and extra-terminal domain (BET) family comprising BRD2, BRD3, BRD4 and BRDT is involved in transcriptional regulation of cancer-related genes and has been recognized as a therapeutic target in many cancer types, such as NUT midline carcinoma (NMC) 3 and acute myeloid leukemia (AML) 4 . JQ1, an inhibitor of BET proteins that binds the acetyllysine (Kac)-binding pocket of bromodomain 3 , has been shown to selectively suppress the expression of tumor-promoting genes in cancer cells and emerges as a promising anti-cancer therapeutic drug 3,5–9 . Since studies on BET inhibition mechanisms have mostly focused on the correlation between BRD4 genomic occupancy and JQ1-induced transcriptional changes 5,10 , little is known on how BRD2 and hyperacetylated histone H4, as the direct chromatin target of BET proteins, engage in the cancer-related pathways.…”

Emerging roles of and therapeutic strategies targeting BRD4 in cancer

“…Bromodomains are highly conserved domains that are made up of approximately 110 amino acids and are composed of a left-handed bundle of four alpha helices, which are linked by ZA and BC loops that vary in sequence between the bromodomain proteins. Despite variations in the ZA and BC loops, amino acid residues involved in acetyl lysine binding including asparagine (Asn) and tyrosine (Tyr) are conserved in bromodomains [3–6]. Bromodomain-containing proteins function as primary readers of acetylated lysine residues on the N- terminal tails of histones [7].…”

“…Sixty-one bromodomains (BrD) are present in the human genome representing eight subfamilies that classify members within the group. This review will focus on members belonging to subfamily II, the Bromo- and Extra-Terminal domain (BET) protein family [3–6]. …”