BRD4 is a newly characterized transcriptional regulator that represses autophagy and lysosomal function

Wen, Xin; Klionsky, Daniel J.

doi:10.1080/15548627.2017.1364334

Cited by 27 publications

(26 citation statements)

References 12 publications

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“…Based on the results of the regulatory effects of BRD4 on 3 important factors as described above, a possibility exists that BRD4 might regulate MMP-13 in diabetic condition (35,38,39). In this study, we found that BRD4 knockdown resulted in decreased MMP-13 level under AGEs-BSA-induced diabetic stress, which was coincident with the effect of JQ1 on MMP-13 in NPCs.…”

Section: Disscusionsupporting

confidence: 66%

BRD4 inhibition regulates MAPK, NF‐κB signals, and autophagy to suppress MMP‐13 expression in diabetic intervertebral disc degeneration

Wang

Chen³

et al. 2019

FASEB j.

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Diabetes mellitus may lead to intervertebral disc degeneration (IVDD). Matrix metalloproteinase‐13 (MMP‐13) is one of the major catabolic factors in extracellular matrix (ECM) metabolism of nucleus pulposus cells (NPCs) and contributes to diabetic IVDD. Bromodomain‐containing protein 4 (BRD4) is a member of the bromodomain and extraterminal protein family and is implicated in chronic inflammation. Here, we report that the expression of BRD4 and MMP‐13 was elevated in diabetic nucleus pulposus tissues as well as in advanced glycation end products (AGEs)‐treated NPCs; also, the regulatory effect of BRD4 on MMP‐13 was studied. We found that MMP‐13 was regulated by MAPK and NF‐κB signaling as well as autophagy in AGEs‐treated NPCs. Next, we explored the role of BRD4 in regulation of MAPK, NF‐κB signaling, and autophagy. The results showed that BRD4 is the upstream regulator of all of these 3 factors, and inhibition of BRD4 may suppress MAPK and NF‐κB signaling while activating autophagy in AGEs‐treated NPCs. Finally, we demonstrated that BRD4 inhibition may suppress MMP‐13 expression in diabetic NPCs in vitro as well as in vivo; meanwhile, it may preserve ECM in diabetic rats. Our study demonstrates that inhibition of BRD4 may suppress MAPK and NF‐κB signaling and activate autophagy to suppress MMP‐13 expression in diabetic IVDD, and diabetic IVDD may be compromised by BRD4 inhibitors.—Wang, J., Hu, J., Chen, X., Huang, C., Lin, J., Shao, Z., Gu, M., Wu, Y., Tian, N., Gao, W., Zhou, Y., Wang, X., Zhang, X. BRD4 inhibition regulates MAPK, NF‐κB signals, and autophagy to suppress MMP‐13 expression in diabetic intervertebral disc degeneration. FASEB J. 33, 11555–11566 (2019). http://www.fasebj.org

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Section: Disscusionsupporting

confidence: 66%

BRD4 inhibition regulates MAPK, NF‐κB signals, and autophagy to suppress MMP‐13 expression in diabetic intervertebral disc degeneration

Wang

Chen³

et al. 2019

FASEB j.

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“…The biological implications of overexpressed BRD4 in GIST were supported by our findings that BRD4‐silenced cell lines demonstrated decreased cell growth and migration. Although overexpressed BRD4 has emerged as a potential therapeutic target in various cancer types, knowledge about the biology of BRD4 inhibition in GIST cell and xenograft models is scant . One such mechanism hypothesized to be involved in imatinib resistance in GIST is the activation of PI3K/AKT signalling .…”

Section: Discussionmentioning

confidence: 99%

“…BRD4 is crucially involved in several cellular processes, including the progression of the cell cycle, cell growth control, apoptosis and tumour initiation . BRD4 is often overexpressed and clinically associated with various human cancers via its elevation of the expression and enhancement of the oncogenic functions of major proteins in cancer, such as aldehyde dehydrogenases (ALDH) in ovarian cancer, androgen receptor (AR) and ETS‐related gene (ERG) in prostate cancer and c‐Myc in leukaemia . BRD4 was shown to regulate PTEN and the PI3K/AKT pathway .…”

Section: Introductionmentioning

confidence: 99%

Bromodomain and extraterminal domain inhibitor enhances the antitumor effect of imatinib in gastrointestinal stromal tumours

Sun²,

et al. 2020

J Cellular Molecular Medi

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In gastrointestinal stromal tumours (GISTs), the function of bromodomain‐containing 4 (BRD4) remains underexplored. BRD4 mRNA abundance was quantified in GISTs. In the current study, we investigated the role of BRD4 in GISTs. Our results show a significant enhancement in BRD4 mRNA and a shift from very low‐risk/low‐risk to high‐risk levels as per NCCN specifications. Overexpression of BRD4 correlated with unfavourable genotype, nongastric location, enhanced risk and decreased disease‐free survival, which were predicted independently. Knockout of BRD4 in vitro suppressed KIT expression, which led to inactivation of the KIT/PI3K/AKT/mTOR pathway, impeded migration and cell growth and made the resistant GIST cells sensitive to imatinib. The expression of KIT was repressed by a BRD4 inhibitor JQ1, which also induced myristoylated‐AKT‐suppressible caspases 3 and 9 activities, induced LC3‐II, exhibited dose‐dependent therapeutic synergy with imatinib and attenuated the activation of the PI3K/AKT/mTOR pathway. In comparison with their single therapy, the combination of JQ1/imatinib more efficiently suppressed the growth of xenografts and exhibited a reduction in KIT phosphorylation, a decrease in Ki‐67 and in the levels of phosphorylated PI3K/AKT/mTOR and enhanced TUNEL staining. Thus, we characterized the biological, prognostic and therapeutic implications of overexpressed BRD4 in GIST and observed that JQ1 suppresses KIT transactivation and nullifies the activation of PI3K/AKT/mTOR, providing a potential strategy for treating imatinib‐resistant GIST through dual blockade of KIT and BRD4.

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“…Autophagy is increased in the pathological process of IDD and alleviates the matrix catabolism induced by TNF‐α and IL‐1β (Gruber, Hoelscher, Ingram, Bethea, & Hanley, 2015; Li et al, 2018; Xu et al, 2015; Ye et al, 2011; Ye et al, 2013). Moreover, BRD4 has been reported to repress autophagy and lysosomal function, while BRD4 knockdown enhances autophagy (Sakamaki & Ryan, 2017; Sakamaki et al, 2017; Wen & Klionsky, 2017). Another BRD4 inhibitor, 9f, can induce AMPK‐modulated autophagy‐associated cell death in breast cancer (Ouyang et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…BRD4, a member of the bromodomain and extra‐terminal domain (BET) family, is emerging as a promising therapeutic target for cancer and inflammation (Hajmirza et al, 2018; Jin et al, 2018). BRD4 is a newly characterized transcriptional regulator and has been found to repress autophagy and lysosomal function by negatively regulating the expression of autophagy or lysosome‐related genes (Huang et al, 2018; Sakamaki & Ryan, 2017; Sakamaki et al, 2017; Wen & Klionsky, 2017). Knockdown of BRD4 or downregulation of BRD4 activity by its inhibitor JQ1 enhances autophagic flux (Campbell et al, 2018; Ouyang et al, 2017).…”

Section: Introductionmentioning

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 is a newly characterized transcriptional regulator that represses autophagy and lysosomal function

Cited by 27 publications

References 12 publications

BRD4 inhibition regulates MAPK, NF‐κB signals, and autophagy to suppress MMP‐13 expression in diabetic intervertebral disc degeneration

BRD4 inhibition regulates MAPK, NF‐κB signals, and autophagy to suppress MMP‐13 expression in diabetic intervertebral disc degeneration

Bromodomain and extraterminal domain inhibitor enhances the antitumor effect of imatinib in gastrointestinal stromal tumours

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

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