BET inhibitors block pancreatic stellate cell collagen I production and attenuate fibrosis in vivo

Kumar, Krishan; DeCant, Brian; Grippo, Paul J.; Hwang, Rosa F.; Bentrem, David J.; Ebine, Kazumi; Munshi, Hidayatullah G.

doi:10.1172/jci.insight.88032

Cited by 51 publications

(52 citation statements)

References 50 publications

(98 reference statements)

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“…These results, together with our earlier studies evaluating the effect of BET inhibitors on pancreatic cancer cells and PSCs 7,22 , provide impetus for the evaluation of BET inhibitors in patients with pancreatic cancer.…”

Section: Discussionmentioning

confidence: 53%

“…We have recently also shown that BET inhibitors can normalize the stroma by inducing stellate cells to become quiescent as reflected by re-accumulation of lipid droplets, decreased collagen production and decreased α-SMA expression 7 . As we now show that BET inhibitors decrease PD-L1 expression, and since BET inhibitors can enhance response to anti-PD-1 antibody in MYC-expressing lymphoma tumors 15 , it is possible that BET inhibitors may also enhance response to immune checkpoint inhibitors in pancreatic cancer.…”

Section: Discussionmentioning

confidence: 92%

“…Since we have published that BET inhibitors can repress c-MYC levels both in the stellate cell line and in PDAC cells 7,22,23 , we evaluated the role of c-MYC in IFN-γ-induced PD-L1 mRNA expression. Suppressing c-MYC in primary PSCs and in the stellate cell line did not decrease IFN-γ-induced PD-L1 expression (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Interplay between interferon regulatory factor 1 and BRD4 in the regulation of PD-L1 in pancreatic stellate cells

Ebine

Kumar

Pham

et al. 2018

Sci Rep

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The fibrotic reaction is a characteristic feature of human pancreatic ductal adenocarcinoma (PDAC) tumors. It is associated with activation and proliferation of pancreatic stellate cells (PSCs), which are key regulators of fibrosis in vivo. While there is increasing interest in the regulation of PD-L1 expression in cancer and immune cells, the expression and regulation of PD-L1 in other stromal cells, such as PSCs, has not been fully evaluated. Here we show that PSCs in vitro express higher PD-L1 mRNA and protein levels compared to the levels present in PDAC cells. We show that inhibitors targeting bromodomain and extra-terminal (BET) proteins and BRD4 knockdown decrease interferon-γ (IFN-γ)-induced PD-L1 expression in PSCs. We also show that c-MYC, one of the well-established targets of BET inhibitors, does not mediate IFN-γ-regulated PD-L1 expression in PSCs. Instead we show that interferon regulatory factor 1 (IRF1) mediates IFN-γ-induced PD-L1 expression in PSCs. Finally, while we show that BET inhibitors do not regulate IFN-γ-induced IRF1 expression in PSCs, BET inhibitors decrease binding of IRF1 and BRD4 to the PD-L1 promoter. Together, these results demonstrate the interplay between IRF1 and BRD4 in the regulation of PD-L1 in PSCs.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 92%

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Interplay between interferon regulatory factor 1 and BRD4 in the regulation of PD-L1 in pancreatic stellate cells

Ebine

Kumar

Pham

et al. 2018

Sci Rep

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“…Recently, the ability of JQ1 to block cardiac fibrosis in the TAC model was confirmed by an independent group, and was associated with reduced endothelial to mesenchymal transition 46 . JQ1 has also been shown to blunt fibrosis in other organ systems, including lung [47][48][49] , kidney 50 , liver and pancreas 51,52 . Collectively, the data underscore the therapeutic potential of BET inhibitors for the treatment of diverse fibrotic diseases.…”

Section: Discussionmentioning

confidence: 99%

Dynamic chromatin targeting of BRD4 stimulates cardiac fibroblast activation

Stratton

Bagchi

Riching

et al. 2019

Preprint

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Small molecule inhibitors of the acetyl-histone binding protein BRD4 have been shown to block cardiac fibrosis in pre-clinical models of heart failure (HF). However, the mechanisms by which BRD4 promotes pathological myocardial fibrosis remain unclear. Here, we demonstrate that BRD4 functions as an effector of TGF-β signaling to stimulate conversion of quiescent cardiac fibroblasts into Periostin (Postn)-positive cells that express high levels of extracellular matrix.BRD4 undergoes stimulus-dependent, genome-wide redistribution in cardiac fibroblasts, becoming enriched on a subset of enhancers and super-enhancers, and leading to RNA polymerase II activation and expression of downstream target genes. Employing the SERTA domain-containing protein 4 (Sertad4) locus as a prototype, we demonstrate that dynamic chromatin targeting of BRD4 is controlled, in part, by p38 mitogen-activated protein kinase, and provide evidence of a novel function for Sertad4 in TGF-β-mediated cardiac fibroblast activation.These findings define BRD4 as a central regulator of the pro-fibrotic cell state of cardiac fibroblasts, and establish a signaling circuit for epigenetic reprogramming in HF.

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“…This is consistent with previous reports indicating a positive role of BETs in FMT. These studies showed that BET family inhibitors mitigated FMT and fibrosis in vital organs such as lung, liver, pancreas, and heart [27][28][29]40 . Our study distinguishes from these reports by addressing the unanswered questions: 1) Whether BETs regulate PDGFRs were not known; 2) a BET regulation of PLK4 (or PLK1) expression remained unexplored.…”

Section: Discussionmentioning

confidence: 97%

A non-canonical role and regulations of polo-like kinase-4 in fibroblast cell-type transition

Urabe

Zhang

et al. 2019

Preprint

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Fibroblast-to-myofibroblast transition (FMT) is central to fibrosis. A divergent member of the polo-like kinase family, PLK4 is known for its canonical role in centriole duplication. Whether this mitotic factor regulates cell type transitions was underexplored. Here we investigated PLK4's activation and expression and regulations thereof in platelet-derived growth factor (PDGF)induced FMT of rat aortic adventitial fibroblasts.PLK4 inhibition (with centrinone-B or siRNA) diminished not only PDGF AA-induced proliferation/migration, but also smooth muscle -actin and its transcription factor serum response factor's activity. While PDGFR inhibition abrogated AA-stimulated PLK4 activation (phosphorylation) and mRNA/protein expression, inhibition of p38 downstream of PDGFR had a similar effect. Further, the transcription of PLK4 (and PDGFR) was blocked by pan-inhibition of the bromo/extraterminal-domains chromatin-bookmark readers (BRD2, BRD3, BRD4), an effect herein determined via siRNAs as mainly mediated by BRD4. In vivo, periadventitial administration of centrinone-B reduced collagen content and thickness of the adventitia in a rat model of carotid artery injury.Thus, we identified a non-canonical role for PLK4 in FMT and its regulation by a BRD4/PDGFR-dominated pathway. This study implicates a potential PLK4-targeted antifibrotic intervention.

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BET inhibitors block pancreatic stellate cell collagen I production and attenuate fibrosis in vivo

Cited by 51 publications

References 50 publications

Interplay between interferon regulatory factor 1 and BRD4 in the regulation of PD-L1 in pancreatic stellate cells

Interplay between interferon regulatory factor 1 and BRD4 in the regulation of PD-L1 in pancreatic stellate cells

Dynamic chromatin targeting of BRD4 stimulates cardiac fibroblast activation

A non-canonical role and regulations of polo-like kinase-4 in fibroblast cell-type transition

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