Functions of bromodomain-containing proteins and their roles in homeostasis and cancer

Fujisawa, Takao; Filippakopoulos, P.

doi:10.1038/nrm.2016.143

Cited by 475 publications

(506 citation statements)

References 191 publications

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“…JQ1 and other inhibitors of epigenetic (BET- (72,73). BETcontaining proteins recognize specific acK residues on histones and transcription factors such as NF-κB (32)(33)(34)(35)72).…”

Section: Discussionmentioning

confidence: 99%

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Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1

Fahey

Stancill

Smith

et al. 2018

Journal of Biological Chemistry

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Endogenous nitric oxide (NO) generated by inducible NO synthase (iNOS) promotes glioblastoma cell proliferation and invasion, and also plays a key role in glioblastoma resistance to chemotherapy and radiotherapy. Non-ionizing photodynamic therapy (PDT) has anti-tumor advantages over conventional glioblastoma therapies. Our previous studies revealed that glioblastoma U87 cells upregulate iNOS after a photodynamic challenge and that resulting NO not only increased resistance to apoptosis, but rendered surviving cells more proliferative and invasive. These findings were largely based on the effects of inhibiting iNOS activity and scavenging NO. Demonstrating now that iNOS expression in photostressed U87 cells is mediated by NF-κB, we hypothesized that (i) recognition of acetylated lysine (acK) on NF-κB p65/Rel A by bromodomain and extra-terminal (BET) protein Brd4 is crucial, and (ii) by suppressing iNOS expression, a BET inhibitor (JQ1) would attenuate the negative effects of photostress. The following evidence was obtained: (i) Like iNOS, Brd4 protein and p65-acK levels increased several fold in photostressed cells; (ii) JQ1 at minimally toxic concentrations had no effect on Brd4 or p65-acK upregulation after PDT, but strongly suppressed iNOS, survivin, and Bcl-xL upregulation, along with the growth and invasion spurt of PDTsurviving cells; (iii) JQ1 inhibition of NO production in photostressed cells closely paralleled that of growth/invasion inhibition; (iv) At 1% the concentration of iNOS inhibitor 1400W, JQ1 reduced post-PDT cell aggressiveness to a far greater extent. This is the first evidence for BET inhibitor targeting of iNOS expression in cancer cells and how such targeting can markedly improve therapeutic efficacy.

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“…JQ1 and other inhibitors of epigenetic (BET- (72,73). BETcontaining proteins recognize specific acK residues on histones and transcription factors such as NF-κB (32)(33)(34)(35)72).…”

Section: Discussionmentioning

confidence: 99%

“…BETcontaining proteins recognize specific acK residues on histones and transcription factors such as NF-κB (32)(33)(34)(35)72). Recent seminal studies by Chen et al (30,31), using A549 lung cancer cells, revealed that Brd4 binding to acK310 on the p65 subunit of NF-κB maintains the latter in an active form.…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1

Fahey

Stancill

Smith

et al. 2018

Journal of Biological Chemistry

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“…In addition to BPTF, there are more than 40 diverse proteins containing BRDs; 57 65 Notably, based on promising results in murine models, BRD proteins have become targets for drug development and translation. 66,67 In aggregate, we propose that haploinsufficiency of BPTF results in an augmented neuronal death, which likely occurs mainly during the postnatal period and manifests with acquired microcephaly and neurodevelopmental abnormalities.…”

Section: Discussionmentioning

confidence: 99%

Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features

Stankiewicz

Khan

Szafrański

et al. 2017

The American Journal of Human Genetics

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Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24.2. The BPTF variants were found in unrelated individuals aged between 2.1 and 13 years, who manifest variable degrees of developmental delay/intellectual disability (10/10), speech delay (10/10), postnatal microcephaly (7/9), and dysmorphic features (9/10). Using CRISPR-Cas9 genome editing of bptf in zebrafish to induce a loss of gene function, we observed a significant reduction in head size of F0 mutants compared to control larvae. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone H3 (PH3) staining to assess apoptosis and cell proliferation, respectively, showed a significant increase in cell death in F0 mutants compared to controls. Additionally, we observed a substantial increase of the ceratohyal angle of the craniofacial skeleton in bptf F0 mutants, indicating abnormal craniofacial patterning. Taken together, our data demonstrate the pathogenic role of BPTF haploinsufficiency in syndromic neurodevelopmental anomalies and extend the clinical spectrum of human disorders caused by ablation of chromatin remodeling complexes.

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“…This results in a relative opening of chromatin, and histone acetylation is broadly associated with activate transcription. Acetylated lysine residues are “read” or recognized by bromodomain-containing proteins, which in addition to a bromodomain, often contain a variety of other functional domains that allow for HAT activity, DNA binding, histone methyltransferase activity, helicase activity, ATPase activity and more (reviewed in (81)).…”

Section: Regulation Of Chromatin Modification By Endogenous Metabolitmentioning

confidence: 99%

Metabolic programming of the epigenome: host and gut microbial metabolite interactions with host chromatin

Krautkramer

Dhillon

Denu

et al. 2017

Translational Research

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The mammalian gut microbiota has been linked to host developmental, immunologic, and metabolic outcomes. This collection of trillions of microbes inhabits the gut and produces a myriad of metabolites, which are measurable in host circulation and contribute to the pathogenesis of human diseases. The link between endogenous metabolite availability and chromatin regulation is a well-established and active area of investigation, however, whether microbial metabolites can elicit similar effects is less understood. In this review, we focus on seminal and recent research that establishes chromatin regulatory roles for both endogenous and microbial metabolites. We also highlight key physiologic and disease settings where microbial metabolite-host chromatin interactions have been established and/or may be pertinent.

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Functions of bromodomain-containing proteins and their roles in homeostasis and cancer

Cited by 475 publications

References 191 publications

Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1

Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1

Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features

Metabolic programming of the epigenome: host and gut microbial metabolite interactions with host chromatin

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