Targeting BET Bromodomains for Cancer Treatment

Jung, Marie; Gelato, Kathy A.; Fernández-Montalván, Amaury E.; Siegel, Stephan; Haendler, Bernard

doi:10.2217/epi.14.91

Cited by 136 publications

(116 citation statements)

References 119 publications

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“…Inhibition of BRD4, a component of super-enhancers, resulted in a dramatic decrease of c-MYC expression and an impact on cancer cell proliferation (Jung et al, 2015; Loven et al, 2013; Shi et al, 2013). Our finding of RACK7 and KDM5C regulation of super-enhancers suggests that the cancer phenotypes caused by loss of RACK7 and KDM5C might be in part due to overactivation of certain super-enhancers, such as the one located in the S100A Cluster I.…”

Section: Discussionmentioning

confidence: 99%

Suppression of Enhancer Overactivation by a RACK7-Histone Demethylase Complex

Shen

Guo

et al. 2016

Cell

146

191

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Summary Regulation of enhancer activity is important for controlling gene expression programs. Here we report that a biochemical complex that contains a potential chromatin reader, RACK7 and the histone lysine 4 tri-methyl (H3K4me3)-specific demethylase KDM5C occupies many active enhancers, including almost all super-enhancers. Loss of RACK7 or KDM5C results in overactivation of enhancers, characterized by the deposition of H3K4me3 and H3K27Ac, together with increased transcription of eRNAs and nearby genes. Furthermore, loss of RACK7 or KDM5C leads to de-repression of S100A oncogenes and various cancer-related phenotypes. Our findings reveal a RACK7/KDM5C-regulated, dynamic interchange between histone H3K4me1 and H3K4me3 at active enhancers, representing an additional layer of regulation of enhancer activity. We propose that RACK7/KDM5C functions as an enhancer “brake” to ensure appropriate enhancer activity, which, when compromised, could contribute to tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

Suppression of Enhancer Overactivation by a RACK7-Histone Demethylase Complex

Shen

Guo

et al. 2016

Cell

146

191

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“…In addition, based on our overall and progression-free survival curve analyses, prognosis appears to be better correlated with amplification rather than mRNA expression, suggesting a potential collaborative role of co-amplified genes in the amplicons. Despite being a part of amplicons, there are several studies demonstrating the importance of NSD3, CHD8 and BRD4 in oncological processes (27)(28)(29)(30)(31), and it is noteworthy that amplicons may not necessarily contain only one oncogene, but may act as a unit with several genes of importance (26). Future knockdown of NSD3, BRD4 and CHD8 or treatment of HGSC displaying pathway amplification with BRD4-specific small-molecule inhibitors are required to confirm the growth-promoting properties of specific gene amplification in patients with pelvic HGSC.…”

Section: Discussionmentioning

confidence: 99%

Amplification of the NSD3‑BRD4‑CHD8 pathway in pelvic high‑grade serous carcinomas of tubo‑ovarian and endometrial origin

Jones

Lin

2017

mol clin onc

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Abstract. Identification of novel therapeutics in pelvic high-grade serous carcinoma (HGSC) has been hampered by a paucity of actionable point mutations in target genes. The aim of the present study was to investigate the extent of amplification of the therapeutically targetable NSD3-CHD8-BRD4 pathway in pelvic HGSC, and to determine whether amplification is associated with worse prognosis. The Cancer Genome Atlas (TCGA) ovarian and endometrial cancer cohorts were retrospectively analyzed via online data-mining tools to test the association of NSD3, CHD8 and BRD4 genomic alterations with survival of pelvic HGSC patients. It was demonstrated that amplification of the NSD3-CHD8-BRD4 pathway in the ovarian HGSC cohort (observed in 18% of the cases, 88/489) was significantly associated with worse overall and progression-free survival compared with non-amplified cases. In addition, amplification of NSD3, CHD8 and BRD4 also occurred in 9% (21/232) of overall endometrial cancer TCGA cases, which was associated with worse overall survival. In the endometrial cancer TCGA cohort, NSD3, CHD8 and BRD4 amplification occurred specifically in the serous carcinoma (25%, 13/53) and 'serous-like' copy number high endometrial carcinoma (33%, 20/60) subgroups, compared with the polymerase e (0%, 0/17), microsatellite instability high (0%, 0/65) or low copy number (1%, 1/90) subgroups. These findings support the hypothesis that amplification of the NSD3-BRD4-CDH8 axis is frequent in pelvic HGSC of both ovarian and endometrial origin, and that this pathway is potentially targetable in a subset of HGSC patients.

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“…The BET subfamily of bromodomain-containing proteins is involved in a number of hematological and solid tumors (15,17). Currently, several active clinical trials aiming to treat malignancies are using BET inhibitors, such as FT-1101, ZEN003694, BMS-986158, INCB054329, RVX-208, I-BET 762, OTX 015, CPI-0610, and TEN-010 (www.clinicaltrials.gov).…”

Section: Discussionmentioning

confidence: 99%

“…This led to clinical studies focusing mostly on the treatment of leukemia and lymphoma. As a result of these studies, the first encouraging signs of efficacy have already been reported (17). Furthermore, previous studies showed that BET inhibitors also control neuronal differentiation and cause an autism-like syndrome (18).…”

mentioning

confidence: 82%

Bromodomain and Extra-terminal (BET) Protein Inhibitors Suppress Chondrocyte Differentiation and Restrain Bone Growth

Niu

Shao

Yan

et al. 2016

Journal of Biological Chemistry

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Edited by Xiao-Fan WangSmall molecule inhibitors for bromodomain and extra-terminal (BET) proteins have recently emerged as potential therapeutic agents in clinical trials for various cancers. However, to date, it is unknown whether these inhibitors have side effects on bone structures. Here, we report that inhibition of BET bromodomain proteins may suppress chondrocyte differentiation and restrain bone growth. We generated a luciferase reporter system using the chondrogenic cell line ATDC5 in which the luciferase gene was driven by the promoter of Col2a1, an elementary collagen of the chondrocyte. The Col2a1-luciferase ATDC5 system was used for rapidly screening both activators and repressors of human collagen Col2a1 gene expression, and we found that BET bromodomain inhibitors reduce the Col2a1-luciferase. Consistent with the luciferase assay, BET inhibitors decrease the expression of Col2a1. Bromodomain and extra-terminal (BET)2 proteins (containing four mammalian members, BRD2, BRD3, BRD4, and BRDT) function as key epigenetic readers by recognizing histone acetylation through binding to ⑀-N-lysine acetylation motifs of histone, such as Lys-5, Lys-12, and Lys-16 residues of H4 histone (1, 2) and Lys-27 residues of H3 histone (3). The BET proteins interact with the positive transcription elongation factor P-TEF␤ and RNA polymerase II (Pol II) to facilitate gene transcription (4 -6). A list of drugs, such as I-BET151, I-BET762, PFI-1, and (ϩ)-JQ1, were discovered to target BET proteins and block the interaction between BET proteins and acetyl-lysine of histones (2, 7).BET proteins and BET inhibitors have been reported to be involved in a variety of biological processes. Pharmacological inhibition of BET proteins lowers the expression of key transcription factors such as oncogene c-MYC (8), clamps the transductions of PI3K signaling (9), inhibits Gli1 transcription and Hedgehog pathway (10), blocks transcription in neurons (11), represses VEGF-induced angiogenesis and vascular permeability (12), reduces cell viability of osteosarcoma cells and inhibits osteoblastic differentiation (13), and restrains osteoclastogenesis (14). Meanwhile, potent BET inhibitors have been identified as showing antitumor efficacy in a number of preclinical cancer models in recent years, including leukemia, multiple myeloma, lymphoma, melanoma, and gastric cancer (15,16). This led to clinical studies focusing mostly on the treatment of leukemia and lymphoma. As a result of these studies, the first encouraging signs of efficacy have already been reported (17). Furthermore, previous studies showed that BET inhibitors also control neuronal differentiation and cause an autism-like syndrome (18). However, BET inhibitors were not examined extensively in these studies to determine their side effects on skeletal bone structures.The long bone is mainly formed through endochondral bone formation, which starts with the formation of a cartilage template from condensed mesenchymal cells. The chondrocytes of the cartilage template proliferate axial...

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Targeting BET Bromodomains for Cancer Treatment

Cited by 136 publications

References 119 publications

Suppression of Enhancer Overactivation by a RACK7-Histone Demethylase Complex

Suppression of Enhancer Overactivation by a RACK7-Histone Demethylase Complex

Amplification of the NSD3‑BRD4‑CHD8 pathway in pelvic high‑grade serous carcinomas of tubo‑ovarian and endometrial origin

Bromodomain and Extra-terminal (BET) Protein Inhibitors Suppress Chondrocyte Differentiation and Restrain Bone Growth

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