BET Inhibition Upregulates SIRT1 and Alleviates Inflammatory Responses

Kokkola, Tarja; Suuronen, Tiina; Pesonen, Maija; Filippakopoulos, P.; Salminen, Antero; Jarho, Elina; Lahtela‐Kakkonen, Maija

doi:10.1002/cbic.201500272

Cited by 18 publications

(26 citation statements)

References 33 publications

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“…The exact mechanism by which BET inhibitors increase endogenous apoA‐I production is not known. Recently, Kokkola et al [] have shown that SIRT1 is activated by BET inhibition via JQ1. This might point toward a role for SIRT1 in increased apoA‐I production caused by BET inhibition.…”

Section: Discussionmentioning

confidence: 99%

Link Between ER-Stress, PPAR-Alpha Activation, and BET Inhibition in Relation to Apolipoprotein A-I Transcription in HepG2 Cells

2017

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Activating transcription factor peroxisome proliferator-activated receptor alpha (PPARα) may increase apoA-I transcription. Furthermore, Bromodomain and Extra-Terminal domain (BET) protein inhibitors increase, whereas Endoplasmic Reticulum (ER) stress decreases apoA-I transcription. We examined possible links between these processes as related to apoA-I transcription in HepG2 cells. JQ1(+), thapsigargin, and GW7647 were used to induce, respectively BET inhibition, ER-stress, and PPARα activation. Expression of ER-stress markers (CHOP, XBP1s) was analyzed by western blotting. PPARα, KEAP1 (marker for BET inhibition), and apoA-I mRNAs were measured using qPCR. ER-stress and BET inhibition both decreased PPARα mRNA expression and activity, but did not interfere with each other, as ER-stress did not change KEAP1 and JQ1(+) did not influence ER-stress marker production. Interestingly, PPARα activation and BET-inhibition diminished ER-stress marker production and rescued apoA-I transcription during existing ER-stress. We conclude that the ER-stress mediated reduction in apoA-I transcription could be partly mediated via the inhibition of PPARα mRNA expression and activity. In addition, BET inhibition increased apoA-I transcription, even if PPARα production and activity were decreased. Finally, both BET inhibition and PPARα activation ameliorate the apoA-I lowering effect of ER-stress and are therefore interesting targets to elevate apoA-I transcription. J. Cell. Biochem. 118:2161-2167, 2017. © 2016 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Link Between ER-Stress, PPAR-Alpha Activation, and BET Inhibition in Relation to Apolipoprotein A-I Transcription in HepG2 Cells

2017

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“…A combination of BET inhibitors (JQ-1 49 ) and SIRT activators (SRT1720, 51 ) was found to alleviate inflammatory response due to the upregulation of SIRT1 by the BETi JQ-1 49 , thus reversing the pro-inflammatory response to SIRT1 inhibition in a cellular lung disease model [ 94 ]. On the other hand, the combination of JQ-1 49 with gamma-secretase inhibitors was shown to be effective against primary human leukemias in vivo [ 95 ].…”

Section: Main Textmentioning

confidence: 99%

Epigenetic polypharmacology: from combination therapy to multitargeted drugs

2016

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The modern drug discovery process has largely focused its attention in the so-called magic bullets, single chemical entities that exhibit high selectivity and potency for a particular target. This approach was based on the assumption that the deregulation of a protein was causally linked to a disease state, and the pharmacological intervention through inhibition of the deregulated target was able to restore normal cell function. However, the use of cocktails or multicomponent drugs to address several targets simultaneously is also popular to treat multifactorial diseases such as cancer and neurological disorders. We review the state of the art with such combinations that have an epigenetic target as one of their mechanisms of action. Epigenetic drug discovery is a rapidly advancing field, and drugs targeting epigenetic enzymes are in the clinic for the treatment of hematological cancers. Approved and experimental epigenetic drugs are undergoing clinical trials in combination with other therapeutic agents via fused or linked pharmacophores in order to benefit from synergistic effects of polypharmacology. In addition, ligands are being discovered which, as single chemical entities, are able to modulate multiple epigenetic targets simultaneously (multitarget epigenetic drugs). These multiple ligands should in principle have a lower risk of drug-drug interactions and drug resistance compared to cocktails or multicomponent drugs. This new generation may rival the so-called magic bullets in the treatment of diseases that arise as a consequence of the deregulation of multiple signaling pathways provided the challenge of optimization of the activities shown by the pharmacophores with the different targets is addressed.

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“…Treatment of cells from asthmatic patients as well as healthy individuals with BET antagonists PFI-1, (+)-JQ1, and I-BET significantly reduced expression of CXCL8 by disrupting the binding of BRD4 and RNAP II to CXCL8 promoter 49 . Interestingly, in another cellular model of lung inflammation, using LPS stimulated A549 lung cell line, a model is proposed in which BET antagonism, and in particular antagonism of BRD2, indirectly reduces inflammation by influencing the expression levels of the histone deacetylase sirtuin 1 (SIRT1) 50 . Also in chronic lung disease idiopathic pulmonary fibrosis, BET antagonism showed positive response attenuating migration, proliferation, and IL-6 release from lung fibroblasts of patients as well as reducing infiltration of pro-inflammatory cells and reducing fibrosis as assessed by histology in a mouse model of lung fibrosis 51 …”

Section: Inflammationmentioning

confidence: 99%

Chemical probes targeting epigenetic proteins: Applications beyond oncology

Ackloo

Brown

Müller³

2017

Epigenetics

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Epigenetic chemical probes are potent, cell-active, small molecule inhibitors or antagonists of specific domains in a protein; they have been indispensable for studying bromodomains and protein methyltransferases. The Structural Genomics Consortium (SGC), comprising scientists from academic and pharmaceutical laboratories, has generated most of the current epigenetic chemical probes. Moreover, the SGC has shared about 4 thousand aliquots of these probes, which have been used primarily for phenotypic profiling or to validate targets in cell lines or primary patient samples cultured in vitro. Epigenetic chemical probes have been critical tools in oncology research and have uncovered mechanistic insights into well-established targets, as well as identify new therapeutic starting points. Indeed, the literature primarily links epigenetic proteins to oncology, but applications in inflammation, viral, metabolic and neurodegenerative diseases are now being reported. We summarize the literature of these emerging applications and provide examples where existing probes might be used.

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BET Inhibition Upregulates SIRT1 and Alleviates Inflammatory Responses

Cited by 18 publications

References 33 publications

Link Between ER-Stress, PPAR-Alpha Activation, and BET Inhibition in Relation to Apolipoprotein A-I Transcription in HepG2 Cells

Link Between ER-Stress, PPAR-Alpha Activation, and BET Inhibition in Relation to Apolipoprotein A-I Transcription in HepG2 Cells

Epigenetic polypharmacology: from combination therapy to multitargeted drugs

Chemical probes targeting epigenetic proteins: Applications beyond oncology

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