The Clinically Used Iron Chelator Deferasirox Is an Inhibitor of Epigenetic JumonjiC Domain-Containing Histone Demethylases

Roatsch, Martin; Hoffmann, Inga; Abboud, Martine I.; Hancock, Rebecca L.; Tarhonskaya, Hanna; Hsu, Kuo–Feng; Wilkins, Sarah E.; Yeh, Tzu Lan; Lippl, Kerstin; Serrer, Kerstin; Moneke, Isabelle; Ahrens, Theresa D.; Robaa, Dina; Wenzler, Sandra; Barthès, Nicolas; Franz, Henriette; Sippl, Wolfgang; Laßmann, Silke; Diederichs, Sven; Schleicher, Erik; Schofield, Christopher J.; Kawamura, Akane; Schüle, Roland; Jung, Manfred

doi:10.1021/acschembio.9b00289

Cited by 22 publications

(18 citation statements)

References 74 publications

(184 reference statements)

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“…18,68 Interestingly, in this assay the extracellular iron chelator DFX functions as a pan-HI, in contrast to its reported PHD-selectivity under some conditions 26,52 ; note more recent work indicates DFX and related compounds are unlikely to be selective for the PHDs. 57 DM-NOFD showed no inhibition of FIH toward OTUB1 HD formation, but interestingly nevertheless regulated HIF transactivation activity in agreement with previous reports. 7,26 A possible explanation is that the sensitivity of FIH to DM-NOFD depends on its protein substrate.…”

Section: Discussionsupporting

confidence: 92%

“…Typically, most reported HIs, including those in clinical evaluation, are PHD active site iron chelators or 2OG analogs/competitors, though it should be noted that compounds chelating Fe in solution also induce HIF as well as inhibiting other 2OG-dependent oxygenases. 25,57 Because both iron and 2OG are important for cellular energy metabolic homeostasis, we analyzed if the HIs affect cellular energy metabolism under standard cell culture conditions. Extracellular lactate and glucose as well as intracellular ATP levels were quantified in the same HEK293-or Hep3B-derived samples, respectively, following 22 hours of HI treatment.…”

Section: The Majority Of His Do Not Change Cellular Energy Metabolimentioning

confidence: 99%

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HIF hydroxylase inhibitors decrease cellular oxygen consumption depending on their selectivity

et al. 2019

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factor; HRB5rl, human hepatoma Hep3B cells stably transfected with the HIF-dependent Firefly luciferase reporter pH3SVL followed by the Renilla reporter construct pRL-SV40; JNJ-1935, JNJ-42041935; OTUB1, ovarian tumor domain-containing ubiquitin aldehyde binding protein 1; PHD, prolyl-4-hydroxylase domain; SDR, SensorDish Reader; SV40, simian virus 40; 2OG, 2-oxoglutarate. AbstractPharmacologic HIF hydroxylase inhibitors (HIs) are effective for the treatment of anemia in chronic kidney disease patients and may also be beneficial for the treatment of diseases such as chronic inflammation and ischemia-reperfusion injury. The selectivities of many HIs for HIF hydroxylases and possible off-target effects in cellulo are unclear, delaying the translation from preclinical studies to clinical trials. We developed a novel assay that discriminates between the inhibition of HIF-α prolyl-4-hydroxylase domain (PHD) enzymes and HIF-α asparagine hydroxylase factor inhibiting HIF (FIH). We characterized 15 clinical and preclinical HIs, categorizing them into pan-HIF-α hydroxylase (broad spectrum), PHD-selective, and FIHselective inhibitors, and investigated their effects on HIF-dependent transcriptional regulation, erythropoietin production, and cellular energy metabolism. While energy homeostasis was generally maintained following HI treatment, the pan-HIs led to a stronger increase in pericellular pO 2 than the PHD/FIH-selective HIs. Combined knockdown of FIH and PHD-selective inhibition did not further increase pericellular pO 2 . Hence, the additional increase in pericellular pO 2 by pan-over PHD-selective HIs likely reflects HIF hydroxylase independent off-target effects. Overall, these analyses demonstrate that HIs can lead to oxygen redistribution within the cellular microenvironment, which should be considered as a possible contributor to HI effects in the treatment of hypoxia-associated diseases. K E Y W O R D Sanemia, hypoxia, 2-oxoglutarate oxygenase inhibitor, prolyl hydroxylase inhibitor, Roxadustat

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Section: Discussionsupporting

confidence: 92%

Section: The Majority Of His Do Not Change Cellular Energy Metabolimentioning

confidence: 99%

HIF hydroxylase inhibitors decrease cellular oxygen consumption depending on their selectivity

et al. 2019

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“…All cellular stresses induced alterations to the global histone PTM profiles, but to different extents, as revealed by our LC-MS-based analyses of intact histones. Note, we have recently shown that Exjade also causes alterations in histone PTMs, at least in part through inhibition of the JmjC KDMs [30]. The dose-and time-dependencies of these effects were investigated to gain further insight into the effects of hypoxic/ hypoxia-mimetic stresses.…”

Section: Discussionmentioning

confidence: 99%

“…More specific PHD inhibitors, such as IOX2 and FG4592 (Roxadustat, which has been approved for use in some countries and is in late stage clinical trials in others for treatment of renal anaemia) [27,28], are used to replicate aspects of reduced oxygen availability on PHD activity. Hypoxia and hypoxia mimetics are reported to affect epigenetic regulation by changing the activities of histone modifying enzymes and the levels of HIF isoforms [8,12,29,30]. However, differences between the effects of hypoxia and hypoxia mimetics on the levels of histone PTMs have not been determined.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia and hypoxia mimetics differentially modulate histone post-translational modifications

et al. 2020

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Post-translational modifications (PTMs) to the tails of the core histone proteins are critically involved in epigenetic regulation. Hypoxia affects histone modifications by altering the activities of histone-modifying enzymes and the levels of hypoxia-inducible factor (HIF) isoforms. Synthetic hypoxia mimetics promote a similar response, but how accurately the hypoxia mimetics replicate the effects of limited oxygen availability on the levels of histone PTMs is uncertain. Here we report studies on the profiling of the global changes to PTMs on intact histones in response to hypoxia/ hypoxia-related stresses using liquid chromatography-mass spectrometry (LC-MS). We demonstrate that intact protein LC-MS profiling is a relatively simple and robust method for investigating potential effects of drugs on histone modifications. The results provide insights into the profiles of PTMs associated with hypoxia and inform on the extent to which hypoxia and hypoxia mimetics cause similar changes to histones. These findings imply chemically-induced hypoxia does not completely replicate the substantial effects of physiological hypoxia on histone PTMs, highlighting that caution should be used in interpreting data from their use.

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“…A small molecule UNC2170 inhibits 53BP1 binding at the interface of two Tudor domains of a 53BP1 dimer, showing cellular activity by suppressing class switch recombination [173]. Recent research shows that the clinically used iron chelator deferasirox potently inhibit JMJD2A, leading to a high level of histone trimethylation and inhibition of cancer cell growth [174]. What is more, UHRF1 inhibitors as an alternative of DNA demethylation agents can inhibit DNA methylation in cancer therapies [175].…”

Section: Bmt and Tudor Inhibitorsmentioning

confidence: 99%

Small Molecules Targeting the Specific Domains of Histone-Mark Readers in Cancer Therapy

et al. 2020

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Epigenetic modifications (or epigenetic tags) on DNA and histones not only alter the chromatin structure, but also provide a recognition platform for subsequent protein recruitment and enable them to acquire executive instructions to carry out specific intracellular biological processes. In cells, different epigenetic-tags on DNA and histones are often recognized by the specific domains in proteins (readers), such as bromodomain (BRD), chromodomain (CHD), plant homeodomain (PHD), Tudor domain, Pro-Trp-Trp-Pro (PWWP) domain and malignant brain tumor (MBT) domain. Recent accumulating data reveal that abnormal intracellular histone modifications (histone marks) caused by tumors can be modulated by small molecule-mediated changes in the activity of the above domains, suggesting that small molecules targeting histone-mark reader domains may be the trend of new anticancer drug development. Here, we summarize the protein domains involved in histone-mark recognition, and introduce recent research findings about small molecules targeting histone-mark readers in cancer therapy.

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The Clinically Used Iron Chelator Deferasirox Is an Inhibitor of Epigenetic JumonjiC Domain-Containing Histone Demethylases

Cited by 22 publications

References 74 publications

HIF hydroxylase inhibitors decrease cellular oxygen consumption depending on their selectivity

HIF hydroxylase inhibitors decrease cellular oxygen consumption depending on their selectivity

Hypoxia and hypoxia mimetics differentially modulate histone post-translational modifications

Small Molecules Targeting the Specific Domains of Histone-Mark Readers in Cancer Therapy

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