Bromodomain (BrD) Family Members as Regulators of Cancer Stemness—A Comprehensive Review

Abstract

Epigenetic mechanisms involving DNA methylation and chromatin modifications have emerged as critical facilitators of cancer heterogeneity, substantially affecting cancer development and progression, modulating cell phenotypes, and enhancing or inhibiting cancer cell malignant properties. Not surprisingly, considering the importance of epigenetic regulators in normal stem cell maintenance, many chromatin-related proteins are essential to maintaining the cancer stem cell (CSC)-like state. With increased tumor-initiating capacities and self-renewal potential, CSCs promote tumor growth, provide therapy resistance, spread tumors, and facilitate tumor relapse after treatment. In this review, we characterized the epigenetic mechanisms that regulate the acquisition and maintenance of cancer stemness concerning selected epigenetic factors belonging to the Bromodomain (BrD) family of proteins. An increasing number of BrD proteins reinforce cancer stemness, supporting the maintenance of the cancer stem cell population in vitro and in vivo via the utilization of distinct mechanisms. As bromodomain possesses high druggable potential, specific BrD proteins might become novel therapeutic targets in cancers exhibiting de-differentiated tumor characteristics.

Discovery of a Highly Potent and Selective BRD9 PROTAC Degrader Based on E3 Binder Investigation for the Treatment of Hematological Tumors

“…This analysis revealed the enrichment of the KEGG_WNT_SIGNALING_PATHWAY gene set among the downregulated pathways in both examined samples (Figure C). This finding aligns with existing literature suggesting a regulatory role for BRD9 within the Wnt signaling pathway. − To further explore this connection, we conducted the Western Blot analysis to measure the levels of critical proteins in the WNT pathway, including C-myc, β-catenin, and AXIN2 (Figure D). The results indicated an elevation in C-myc levels and a reduction in the expression of β-catenin and AXIN2.…”

“…1-(4-(Piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (33). General procedure D. 3-(6-Bromo-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (36).…”

Binding Mechanism of Inhibitors to BRD4 and BRD9 Decoded by Multiple Independent Molecular Dynamics Simulations and Deep Learning

“…Previous studies have shown that BRD proteins, particularly those of the bromodomain and extraterminal (BET) family, are involved in tumorigenesis, cancers and inflammatory diseases. Moreover, there is growing evidence to suggest that BRDs play a role in the development of various diseases by regulating the transcription of several genes involved in cancer growth and inflammation [9][10][11]; therefore, BRD proteins have been an important target in regard to anti-cancer drug design. In addition, different BRD inhibitors have been designed, some of which are even undergoing clinical trials for both oncology and non-oncology indications [12][13][14][15].…”

Selectivity Mechanism of Pyrrolopyridone Analogues Targeting Bromodomain 2 of Bromodomain-Containing Protein 4 from Molecular Dynamics Simulations

“…However, there are no approved BET inhibitors for therapy as BET inhibition has side effects (for example, thrombocytopenia, anemia, neutropenia, nausea, diarrhea, pneumonia, elevated bilirubin, and fatigue). , Notably, these safety signals are pharmacology-driven and dose-limiting, preventing BET inhibitors from achieving their full potential owing to limited target engagement at their maximum tolerated dose. Pan-BD1 or pan-BD2 inhibitors show better tolerance than pan-BD inhibitors and have reduced side effects. , Nevertheless, the high sequence homology and structural similarity between the BD domains among BET family members have limited the development of selective BD inhibitors. ,,,, Thus, selective BD inhibitors are urgently required for disease treatment.…”

“…18,19 Nevertheless, the high sequence homology and structural similarity between the BD domains among BET family members have limited the development of selective BD inhibitors. 24,26,43,57,58 Thus, selective BD inhibitors are urgently required for disease treatment.…”