Reading Cancer: Chromatin Readers as Druggable Targets for Cancer Treatment

Abstract

The epigenetic machinery deputed to control histone post-translational modifications is frequently dysregulated in cancer cells. With epigenetics being naturally reversible, it represents a good target for therapies directed to restore normal gene expression. Since the discovery of Bromodomain and Extra Terminal (BET) inhibitors, a great effort has been spent investigating the effects of chromatin readers’ inhibition, specifically the class of proteins assigned to bind acetylated and methylated residues. So far, focused studies have been produced on epigenetic regulation, dissecting a specific class of epigenetic-related proteins or investigating epigenetic therapy in a specific tumor type. In this review, recent steps toward drug discovery on the different classes of chromatin readers have been outlined, highlighting the pros and cons of current therapeutic approaches.

Nanoparticles Loaded with the BET Inhibitor JQ1 Block the Growth of Triple Negative Breast Cancer Cells In Vitro and In Vivo

“…Many approaches are currently under investigation, including the search for molecular targets, potential candidates for selective treatments [20]. For this purpose, targeting histone activity in regulating gene expression by acting on epigenome "readers" is a promising approach for the treatment of various malignancies, including TNBC [9,21,22]. In particular, JQ1 is a first-in-class selective BET bromodomain inhibitor [23], which acts by competitively binding with high affinity to the acetyl-lysine hydrophobic pocket of BRD4 [24,25].…”

“…Furthermore, the possibility of co-encapsulation of other active compounds offered by this kind of nanoparticles may represent an additional advancement of the anticancer features of this nanoformulation. Indeed, the recent direction of the research of anticancer use of BET inhibitors suggests the use of combinations with other chemotherapeutics, including associations inside the same delivery biosystems [9,22,38,41,42].…”

“…JQ1 acts by competing with acetylated histone residues, thus removing BET proteins from their chromatin targets. It has been tested for its anticancer effects in both solid and hematological preclinical models of malignancies [4,8,9].…”

Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg

“…Readers are often found as part of multimeric complexes in association with writers and erasers, enabling the dynamic integration of signals that modulate chromatin conformation. 49 , 66 The best characterised epigenetic readers are those that recognise 5mC, acetyl-lysines and methyl-lysines, while there is less information available for other modifications, such as Ser- and Thr- phosphorylation ( Fig. 1 ).…”

Small Molecules Targeting the Specific Domains of Histone-Mark Readers in Cancer Therapy

“…In addition, some proteins are recruited at the site of histone marks to obtain instructions for performing functions. However, whether it is to remove the marks or to recruit proteins to a specific modified site, it is usually necessary for the proteins to recognize the specific histone marks just like a reader [11]. Numerous studies have shown that histone-mark readers often recognize marks through the functional domain contained in itself: such as BRD, CHD, PHD and MBT domains.…”