BRD4 inhibition suppresses cell growth, migration and invasion of salivary adenoid cystic carcinoma

Wang, Limei; Wu, Xiuyin; Wang, Ruolin; Yang, Chengzhe; Li, Zhi; Wang, Cunwei; Zhang, Fenghe; Yang, Pishan

doi:10.1186/s40659-017-0124-9

Cited by 40 publications

(31 citation statements)

References 47 publications

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“…Consistent with a prominent effect of BET inhibition on blocking EndoMT observed herein 11 , JQ1 has been reported to mitigate EMT in carcinomic 17,19 and pulmonary 20 epithelial cells, although without identification of the specific BET family members or BDs involved. Interestingly, a very recent report identified BRD2 as the key regulator of EMT with BRD3 and BRD4 playing an opposite role 21 .…”

Section: Discussionsupporting

confidence: 63%

The BD2 domain of BRD4 is a determinant in EndoMT and vein graft neointima formation

Zhang

Wang

Urabe

et al. 2019

Preprint

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Background: Vein-graft bypass is commonly performed to overcome atherosclerosis but is limited by high failure rates, principally due to neointimal wall thickening. Recent studies reveal that endothelial-mesenchymal transition (EndoMT) is critical for vein-graft neointima formation. BETs are a family of Bromo/ExtraTerminal domains-containing epigenetic reader proteins (BRD2, BRD3, BRD4). They bind acetylated histones through their unique tandem bromodomains (BD1, BD2), facilitating transcriptional complex formation and cell-state transitions. The role for BETs, including individual BRDs and their unique BDs, is not well understood in EndoMT and neointimal formation. Methods and Results:Repression of BRD4 expression abrogated TGFβ1-induced EndoMT, with greater effects than BRD2 or BRD3 knockdown. An inhibitor selective for BD2 in all BETs, but not that for BD1, blocked EndoMT. Moreover, expression of a dominant-negative BRD4specific BD2 fully abolished EndoMT. Concordantly, BRD4 knockdown repressed TGFβ1stimulated increase of ZEB1 proteina transcription factor integral in EndoMT. In vivo, lentiviral gene transfer of either BRD4 shRNA or dominant negative BRD4-specific BD2 mitigated neointimal development in rat jugular veins grafted to carotid arteries. Conclusions:Our data reveal the BD2 domain of BRD4 as a determinant driving EndoMT in vitro and neointimal formation in vivo. These findings provide new insight into BET biology, while offering prospects of specific BET domain targeting as an approach to limiting neointima and extending vein graft patency.

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Section: Discussionsupporting

confidence: 63%

The BD2 domain of BRD4 is a determinant in EndoMT and vein graft neointima formation

Zhang

Wang

Urabe

et al. 2019

Preprint

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“…It can promote cell proliferation, cell-cycle progression, survival and apoptosis resistance [46]. Several of these genes have been indentified, including cyclin D1, Bcl-2 and c-Myc [38,[47][48][49][50][51]. Our results show that BRD4 silencing by targeted shRNAs led to c-Myc downregulation in 786-O cells.…”

Section: Discussionsupporting

confidence: 48%

Bromodomain-Containing Protein 4 (BRD4) Inhibition Sensitizes Palomid 529-Induced Anti-Renal Cell Carcinoma Cell Activity in Vitro and in Vivo

Zhou

Yin

Cheng

et al. 2018

Cell Physiol Biochem

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Background/Aims: Mammalian target of rapamycin (mTOR) is a valuable treatment target of renal cell carcinoma (RCC). Palomid 529 is a novel mTORC1/2 dual inhibitor. Methods: RCC cells were treated with different concentrations of Palomid 529. Cell survival was tested by MTT assay and clonogenicity assay. Cell proliferation was tested by BrdU ELISA assay. Cell apoptosis was tested by the Hoechst-33342 nuclei staining assay and Histone DNA ELISA assay. mTOR signaling was tested by Western blotting assay and co-immunoprecipitation (IP) assay. The SCID mouse 786-O xenograft model was established to test RCC cell growth in vivo. Results: Palomid 529 exerted cytotoxic, anti-proliferative and pro-apoptotic activities in 786-O RCC cells. Palomid 529 disassembled mTORC1/2, causing de-phosphorylation of mTORC1/2 substrates. Bromodomain-containing protein 4 (BRD4) is a primary resistant factor of Palomid 529. Palomid 529-induced 786-O cell apoptosis was sensitized by BRD4 inhibitors or BRD4 silencing, but inhibited with BRD4 over-expression. Palomid 529-induced cytotoxicity in the primary human RCC cells was negatively correlated with BRD4 expression level. In vivo, Palomid 529 i.p. administration inhibited 786-O xenograft tumor growth in SCID mice. Its anti-tumor activity was further sensitized by co-administration of the BRD4 inhibitor JQ1. Cconclusion: Palomid 529 inhibits RCC cell growth in vitro and in vivo. BRD4 inhibition could further sensitize Palomid 529 against RCC cells.

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“…Melatonin has been reported to inhibit NP cell proliferation and matrix remodeling, while ERRFI1 has been found to inhibit proliferation and alleviate inflammation of NP cells (Guo et al, 2019; Li et al, 2017). Numerous reports have revealed that BRD4 promotes cell proliferation in gastric cancer and cutaneous T‐cell lymphoma (Ba et al, 2018; Dong, Hu, Chen, Hu, & Chen, 2018; Kamijo et al, 2017; Wang et al, 2017). Herein, the CCK‐8 and flow cytometry results revealed that JQ1 inhibited proliferation by inducing cell cycle arrest in G0/G1 phase.…”

Section: Discussionmentioning

confidence: 99%

Bromodomain‐containing protein 4 inhibition alleviates matrix degradation by enhancing autophagy and suppressing NLRP3 inflammasome activity in NP cells

Hong

Markova

et al. 2020

Journal Cellular Physiology

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An imbalance between matrix synthesis and degradation is the hallmark of intervertebral disc degeneration while inflammatory cytokines contribute to the imbalance. Bromodomain and extra‐terminal domain (BET) family is associated with the pathogenesis of inflammation, and inhibition of BRD4, a vital member of BET family, plays an anti‐inflammatory role in many diseases. However, it remains elusive whether BRD4 plays a similar role in nucleus pulposus (NP) cells and participates in the pathogenesis of intervertebral disc degeneration. The present study aims to observe whether BRD4 inhibition regulates matrix metabolism by controlling autophagy and NLRP3 inflammasome activity. Besides, the relationship was investigated among nuclear factor κB (NF‐κB) signaling, autophagy and NLRP3 inflammasome in NP cells. Here, real‐time polymerase chain reaction, western blot analysis and adenoviral GFP‐LC3 vector transduction in vitro were used, and it was revealed that BRD4 inhibition alleviated the matrix degradation and increased autophagy in the presence or absence of tumor necrosis factor α. Moreover, p65 knockdown or treatment with JQ1 and Bay11‐7082 demonstrated that BRD4 inhibition attenuated NLRP3 inflammasome activity through NF‐κB signaling, while autophagy inhibition by bafilomycin A1 promoted matrix degradation and NLRP3 inflammasome activity in NP cells. In addition, analysis of BRD4 messenger RNA expression in human NP tissues further verified the destructive function of BRD4. Simply, BRD4 inhibition alleviates matrix degradation by enhancing autophagy and suppressing NLRP3 inflammasome activity through NF‐κB signaling in NP cells.

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BRD4 inhibition suppresses cell growth, migration and invasion of salivary adenoid cystic carcinoma

Cited by 40 publications

References 47 publications

The BD2 domain of BRD4 is a determinant in EndoMT and vein graft neointima formation

The BD2 domain of BRD4 is a determinant in EndoMT and vein graft neointima formation

Bromodomain-Containing Protein 4 (BRD4) Inhibition Sensitizes Palomid 529-Induced Anti-Renal Cell Carcinoma Cell Activity in Vitro and in Vivo

Bromodomain‐containing protein 4 inhibition alleviates matrix degradation by enhancing autophagy and suppressing NLRP3 inflammasome activity in NP cells

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