Targeting the BRD4/FOXO3a/CDK6 axis sensitizes AKT inhibition in luminal breast cancer

Liu, Jingyi; Duan, Zhi-quan; Guo, Weijie; Zeng, Lei; Wu, Yadi; Chen, Yule; Tai, Fang; Wang, Yifan; Lin, Yiwei; Zhang, Qiang; He, Yan-Ling; Deng, Jiong; Stewart, Rachel L.; Wang, Chi; Lin, Ping Chang; Ghaffari, Saghi; Evers, B. Mark; Liu, Suling; Zhou, Ming‐Ming; Zhou, Binhua P.; Shi, Jian

doi:10.1038/s41467-018-07258-y

Cited by 82 publications

(68 citation statements)

References 49 publications

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“…At the same time, somatic mutations in BRD4 (Fig. 4a), which is considered a key oncogene and promising therapeutic target, were also significantly enriched in the CIMP-H subtype [48,49].…”

Section: Resultsmentioning

confidence: 99%

Development and validation of a CIMP-associated prognostic model for hepatocellular carcinoma

Zhang

et al. 2019

EBioMedicine

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BackgroundCpG island methylator phenotype (CIMP), a common biological phenomenon characterized by a subset of concurrently methylated genes, can have an influence on the progression of multiple cancers. However, the potential mechanism of CIMP in hepatocarcinogenesis and its clinical relevance remains only partially understood.Methods: We used a methylation array from the cancer genome atlas (TCGA) to stratify HCC patients into different CIMP subtypes, and evaluated their correlation with clinical characteristics. In addition, mutation, CNV, and transcriptome profiles were also utilized to evaluate the distinctive genomic patterns correlated with CIMP. Finally, a CIMP-associated prognostic model (CPM) was trained and validated using four independent datasets.FindingsA subgroup of patients was identified as having CIMP-H, which was associated with worse OS and DFS. Gene enrichment analysis indicated that the terms “liver cancer with EPCAM up”, “tumor invasiveness up”, “methyltransferase complex”, and “translational initiation” were enriched in CIMP-H subgroup. Notably, somatic mutation analysis indicated that CIMP-H patients presented with a higher mutation burden of BRD4, DDIAS and NOX1. Moreover, four CPM associated genes could significantly categorize patients into low- and high-risk groups in the training dataset and another 3 independent validation datasets. Finally, a nomogram incorporating a classifier based on four mRNAs, pathological M stage and CIMP status was established, which showed a favorable discriminating ability and might contribute to clinical decision-making for HCC.InterpretationOur work highlights the potential clinical application value of CPM in predicting the overall survival of HCC patients and the mechanisms underlying the role of CIMP in hepatocarcinogenesis.FundThis work was supported by the State Key Project on Infectious Diseases of China (2018ZX10723204-003), the National Nature Science Foundation of China (Nos. 81874065, 81500565, 81874149, 81572427, and 81401997), the Hepato-Biliary-Pancreatic Malignant Tumor Investigation Fund of Chen Xiao-ping Foundation for the Development of Science and Technology of Hubei Province (CXPJJH11800001-2018356).

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“…At the same time, somatic mutations in BRD4 (Fig. 4a), which is considered a key oncogene and promising therapeutic target, were also significantly enriched in the CIMP-H subtype [48,49].…”

Section: Resultsmentioning

confidence: 99%

Development and validation of a CIMP-associated prognostic model for hepatocellular carcinoma

Zhang

et al. 2019

EBioMedicine

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“…Given this situation, it is possible that bivalent or multivalent binding of BD proteins is observed in the cell. To date, however, most structures containing native multi-AcK peptides have the AcK residues accommodated in a single BD ( 22 , 40 – 42 ). There are, however, two structures that show binding of two BET BDs to a histone peptide through two closely spaced AcKs ( SI Appendix , Fig.…”

Section: Discussionmentioning

confidence: 99%

Cyclic peptides can engage a single binding pocket through highly divergent modes

Patel

Walport

Walshe

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Cyclic peptide library screening technologies show immense promise for identifying drug leads and chemical probes for challenging targets. However, the structural and functional diversity encoded within such libraries is largely undefined. We have systematically profiled the affinity, selectivity, and structural features of library-derived cyclic peptides selected to recognize three closely related targets: the acetyllysine-binding bromodomain proteins BRD2, -3, and -4. We report affinities as low as 100 pM and specificities of up to 106-fold. Crystal structures of 13 peptide–bromodomain complexes reveal remarkable diversity in both structure and binding mode, including both α-helical and β-sheet structures as well as bivalent binding modes. The peptides can also exhibit a high degree of structural preorganization. Our data demonstrate the enormous potential within these libraries to provide diverse binding modes against a single target, which underpins their capacity to yield highly potent and selective ligands.

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“…Notably, SEs are involved in the drug resistance of breast cancer cells. (Nguyen et al, 2015; Liu et al, 2018; Miano et al, 2018). Although it is still not sure whether SE blockers can reverse drug resistance, they may be good research targets to find novel drugs to treat drug-resistant tumors.…”

Section: Ses In Other Cancersmentioning

confidence: 99%

“…MEK inhibition opens chromatin and establishes super-enhancers at genes required for late myogenic differentiation, through ERK2/MYOG pathways (Yohe et al, 2018). AKT inhibitors (AKTi) induce FOXO3a acetylation as well as BRD4 recognition (Liu et al, 2018). Although SEs generally upregulate oncogene expression, in some cases, they also promote the expression of tumor suppressor genes (Pelish et al, 2015).…”

Section: Future Directionsmentioning

confidence: 99%

Targeting Super-Enhancers as a Therapeutic Strategy for Cancer Treatment

Long

Liu

2019

Front. Pharmacol.

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Super-enhancers (SEs) refer to large clusters of enhancers that drive gene expressions. Recent data has provided novel insights in elucidating the roles of SEs in many diseases, including cancer. Many mechanisms involved in tumorigenesis and progression, ranging from internal gene mutation and rearrangement to external damage and inducement, have been demonstrated to be highly associated with SEs. Moreover, translocation, formation, deletion, or duplication of SEs themselves could lead to tumor development. It has been reported that various oncogenic molecules and pathways are tightly regulated by SEs. Moreover, several clinical trials on novel SEs blockers, such as BET inhibitor and CDK7i, have indicated the potential roles of SEs in cancer therapy. In this review, we highlighted the underlying mechanism of action of SEs in cancer development and the corresponding novel potential therapeutic strategies. It is speculated that targeting SEs could complement the traditional approaches and lead to more effective treatment for cancer patients.

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Targeting the BRD4/FOXO3a/CDK6 axis sensitizes AKT inhibition in luminal breast cancer

Cited by 82 publications

References 49 publications

Development and validation of a CIMP-associated prognostic model for hepatocellular carcinoma

Development and validation of a CIMP-associated prognostic model for hepatocellular carcinoma

Cyclic peptides can engage a single binding pocket through highly divergent modes

Targeting Super-Enhancers as a Therapeutic Strategy for Cancer Treatment

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