Targeting Brd4 for cancer therapy: inhibitors and degraders

Duan, Ying-Chao; Guan, Yu; Qin, Wenping; Zhai, Xiaoyu; Yu, Bin

doi:10.1039/c8md00198g

Cited by 116 publications

(102 citation statements)

References 112 publications

Supporting

Mentioning

101

Contrasting

Unclassified

Order By: Relevance

“…BRD4 inhibitors are potent antivirals signaling in tumorigenesis has been a recent concern of oncologists, and STING agonists have been tested in early clinical trials [68,69]. Moreover, BRD4 is largely acknowledged for its roles in organization of super-enhancers and oncogene expression in cancer [70,71]. We suggest another beneficial effect of BRD4 inhibitors in cancer immunotherapy.…”

Section: Plos Pathogensmentioning

confidence: 87%

BRD4 inhibition exerts anti-viral activity through DNA damage-dependent innate immune responses

Wang

Ming

et al. 2020

PLoS Pathog

View full text Add to dashboard Cite

Chromatin dynamics regulated by epigenetic modification is crucial in genome stability and gene expression. Various epigenetic mechanisms have been identified in the pathogenesis of human diseases. Here, we examined the effects of ten epigenetic agents on pseudorabies virus (PRV) infection by using GFP-reporter assays. Inhibitors of bromodomain protein 4 (BRD4), which receives much more attention in cancer than viral infection, was found to exhibit substantial anti-viral activity against PRV as well as a range of DNA and RNA viruses. We further demonstrated that BRD4 inhibition boosted a robust innate immune response. BRD4 inhibition also de-compacted chromatin structure and induced the DNA damage response, thereby triggering the activation of cGAS-mediated innate immunity and increasing host resistance to viral infection both in vitro and in vivo. Mechanistically, the inhibitory effect of BRD4 inhibition on viral infection was mainly attributed to the attenuation of viral attachment. Our findings reveal a unique mechanism through which BRD4 inhibition restrains viral infection and points to its potent therapeutic value for viral infectious diseases. Author summaryBRD4 has been well investigated in tumorigenesis for its contribution to chromatin remodeling and gene transcription. BRD4 inhibitors are used as promising chemotherapeutic drugs for cancer therapy. Here, we show a unique mechanism through which BRD4 inhibition broadly inhibits attachment of DNA and RNA viruses through DNA damage-dependent antiviral innate immune activation via the cGAS-STING pathway, in both cell culture and an animal model. STING-associated innate immune signaling has been considered to be a new possibility for cancer therapy, and STING agonists have been tested in early clinical trials. Our data identify BRD4 inhibitors as a potent therapy not only for viral infection but also for cancer immunotherapy. PLOS PATHOGENSPLOS Pathogens | https://doi.

show abstract

Section: Plos Pathogensmentioning

confidence: 87%

BRD4 inhibition exerts anti-viral activity through DNA damage-dependent innate immune responses

Wang

Ming

et al. 2020

PLoS Pathog

View full text Add to dashboard Cite

show abstract

“…The bromodomain and extra-terminal domain (BET) family of proteins, especially BRD4 has emerged as regulating multiple genes expression involved in cell cycle, cell growth and inflammation due to their important roles in epigenetic regulation [19,20]. Unbiased genetic screening for a variety of cancers has shown that BRD4 is critical for cell survival and a promising anticancer target [21], such as acute myeloid leukemia [22], glioblastoma [23] and lung adenocarcinoma [24]. In contrast, BRD4 is downregulated in colon [25] and breast cancers [26].…”

Section: Discussionmentioning

confidence: 99%

Caveolin-2 is regulated by BRD4 and contributes to cell growth in pancreatic cancer

et al. 2020

View full text Add to dashboard Cite

Background: The bromodomain and extra-terminal domain (BET) family of proteins, especially BRD4 play an important role in epigenetic regulation, and are essential for cell survival and also are promising anticancer targets. This study aims to analyze the effect of BRD4 on the cell growth and progression of pancreatic cancer and novel mechanisms involved.Methods: Expression of BRD4 in pancreatic cancer and paired adjacent noncancerous tissues from 76 patients was analyzed by western blotting, immunohistochemistry, and real time PCR. Its correlation with the clinicopathological characteristics and prognosis of pancreatic cancer patients was analyzed. The effects of BRD4 on the cell proliferation were detected by colony formation assay and sulforhodamine B assay. Migration and invasion were determined by Transwell assays, and the effect of BRD4 on subcutaneous tumor formation was verified in nude mice. Cell cycle analysis was detected by flow cytometry. The potential downstream targets of BRD4 and related molecular mechanisms were clarified by RNA sequencing, chromatin immunoprecipitation and dual luciferase reporter assay.Results: BRD4 was overexpressed in pancreatic cancer. Biological results showed that BRD4 functioned as tumor promoter, facilitated cell proliferation, migration and invasion in vitro and in vivo. Further, caveolin-2 was selected as the downstream gene of BRD4 by RNA sequencing. Caveolin-2 overexpression can partially reverse the decreased cell growth ability caused by BRD4 knockdown, but did not affect cell migration and invasion. Chromatin immunoprecipitation assay and dual luciferase reporter assay revealed BRD4 could bind to the promoter region of caveolin-2 and upregulate caveolin-2 expression. Clinical data further indicated a positive correlation between BRD4 and caveolin-2 expression. BRD4 (high)/caveolin-2 (high) correlated with shorter overall survival of patients with pancreatic cancer. Multivariate analysis revealed that both BRD4 and caveolin-2 were independent factors. Conclusions:Our findings reveal the oncogenic effects of BRD4 in pancreatic cancer and elucidate a possible mechanism by which BRD4 and caveolin-2 act to enhance cell growth. Targeting the BRD4-caveolin-2 interaction by development of BET inhibitors will be a therapeutic strategy for pancreatic cancer.

show abstract

“…One possible candidate target is BRD4, as discussed above 21 . Numerous BRD4 inhibitors have been generated and they have shown to be effective in inhibiting tumor growth 37,38 . Some of these molecules are currently in Phase I or II clinical trials for cancer treatment 38 .…”

Section: Discussionmentioning

confidence: 99%

“…21 Numerous BRD4 inhibitors have been generated and they have shown to be effective in inhibiting tumor growth. 37,38 Some of these molecules are currently in Phase I or II clinical trials for cancer treatment. 38 The specific requirement of BRD4 in HB tumorigenesis and the mechanisms whereby BRD4 regulates YAP-dependent transcriptional activity should be investigated using similar approaches to those described in the present manuscript.…”

Section: Discussionmentioning

confidence: 99%

“…37,38 Some of these molecules are currently in Phase I or II clinical trials for cancer treatment. 38 The specific requirement of BRD4 in HB tumorigenesis and the mechanisms whereby BRD4 regulates YAP-dependent transcriptional activity should be investigated using similar approaches to those described in the present manuscript. These investigations will eventually provide the biological rationale for testing BRD4 inhibitors for HB treatment.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

CDK9 is dispensable for YAP‐driven hepatoblastoma development

Chen

Kiss

Schaff

et al. 2020

Pediatric Blood & Cancer

View full text Add to dashboard Cite

Background Hepatoblastoma (HB) is the most common pediatric liver malignancy, occurring mainly during the first 4 years of life. Recent studies unraveled the frequent, coordinated activation of Wnt/β‐catenin and YAP/Hippo (where YAP is yes‐associated protein) pathways in human HB samples. Furthermore, it was found that concomitant overexpression of activated forms of β‐catenin and YAP in the mouse liver triggers HB formation in YAP/β‐catenin mice. Cyclin‐dependent kinases 9 (CDK9) is an elongating kinase, which has been shown to mediate YAP‐driven tumorigenesis. The role of CDK9 in HB molecular pathogenesis has not been investigated to date. Methods CDK9 expression was determined in human HB lesions, HB cell lines, and YAP/β‐catenin mouse livers. CDK9 was silenced in human HB cell lines and the effects on growth rate and YAP targets were analyzed. Hydrodynamic transfection of YAPS127A and ∆N90‐β‐catenin together with either shCdk9 or control shLuc (where Luc is luciferase) plasmids was employed to assess the requirement of Cdk9 for HB development in vivo. Results Nuclear immunoreactivity for CDK9 protein was more pronounced in human HB samples and YAP/β‐catenin mouse HB tumor tissues than in corresponding surrounding nontumorous liver tissues. CDK9 protein was also expressed in human HB cell lines. Silencing of CDK9 in human HB cell lines did not lead to consistent effects on HB cell growth or YAP target gene expression. Surprisingly, silencing of Cdk9 led to accelerated liver tumorigenesis in YAP/β‐catenin mice. Conclusion CDK9 is not a major downstream mediator of YAP oncogenic function in HB development and progression.

show abstract

Targeting Brd4 for cancer therapy: inhibitors and degraders

Abstract: This review summarizes recent developments of Brd4 inhibitors and degraders for cancer treatment.

Cited by 116 publications

References 112 publications

BRD4 inhibition exerts anti-viral activity through DNA damage-dependent innate immune responses

BRD4 inhibition exerts anti-viral activity through DNA damage-dependent innate immune responses

Caveolin-2 is regulated by BRD4 and contributes to cell growth in pancreatic cancer

CDK9 is dispensable for YAP‐driven hepatoblastoma development

Contact Info

Product

Resources

About