Annual review of LSD1/KDM1A inhibitors in 2020

Fu, Dong-Jun; Li, Jun

doi:10.1016/j.ejmech.2021.113254

Cited by 27 publications

(17 citation statements)

References 94 publications

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“…Western blotting analyses of nuclear/cytoplasmic fractions showed rapid nuclear re-localization of NF-ΚB after MHV-infection, as expected, already evident at 10 hpi (figure 6A-B). Same analysis for all 9 IRFs (supplementary figure 7A) showed upregulation and nuclear localization of IRF1 and, to a lesser extent, IRF2, whereas the other IRFs showed either no change (IRF5,9) or even decreased nuclear levels (IRF 3,4,6,7,8). Notable is the suppression of IRF3 and IRF7, typically involved in the response to dsRNA and ssRNA, thus confirming the existence of cellular-evasive mechanisms specific to coronaviruses 12,34,35 .…”

Section: Differential Effect Of Lsd1 Inhibition On Macrophage-secreted Cytotoxic Vs Antiviral Activitiesmentioning

confidence: 58%

“…To explore the translational relevance of LSD1 inhibition as a potential treatment for Covid-19 or other coronavirus infections, we compared the activity of DDP with ORY-1001 and dexamethasone. ORY-1001 is an LSD1 inhibitor of the same class of DDP that has completed initial phases of clinical development in the context of hematological malignances 8 . Dexamethasone is the only host-targeting medical treatment approved to date for Covid-19 as it moderately improves survival and effectively dampens the NF-κB-dependent response, but is also suspected to suppress interferon activity thus resulting in prolonged viral shedding [37][38][39] .…”

Section: Lsd1 As a Target To Curb Human Cytokine Storm In Covid-19 While Preserving Antiviral Activitymentioning

confidence: 99%

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Inhibiting LSD1 suppresses coronavirus-induced inflammation but spares innate antiviral activity

Mazzarella

Santoro

Ravasio

et al. 2021

Preprint

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Tissue-resident macrophages exert critical but conflicting effects on the progression of coronavirus infections by secreting both anti-viral type I Interferons and tissue-damaging inflammatory cytokines. Steroids, the only class of host-targeting drugs approved for Covid19, indiscriminately suppress both responses, possibly impairing viral clearance, and provide limited clinical benefit. Here we set up a mouse in vitro co-culture system that reproduces the macrophage response to SARS-CoV2 seen in patients and allows quantitation of inflammatory and antiviral activities. We show that the NFKB-dependent inflammatory response can be selectively inhibited by ablating the lysine-demethylase LSD1, which additionally unleashed interferon-independent ISG activation and blocked viral egress through the lysosomal pathway. These results provide a rationale for repurposing LSD1 inhibitors, a class of drugs extensively studied in oncology, for Covid-19 treatment.

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Section: Differential Effect Of Lsd1 Inhibition On Macrophage-secreted Cytotoxic Vs Antiviral Activitiesmentioning

confidence: 58%

Section: Lsd1 As a Target To Curb Human Cytokine Storm In Covid-19 While Preserving Antiviral Activitymentioning

confidence: 99%

Inhibiting LSD1 suppresses coronavirus-induced inflammation but spares innate antiviral activity

Mazzarella

Santoro

Ravasio

et al. 2021

Preprint

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“…epithelial-mesenchymal transition (EMT), cell proliferation and differentiation or malignant transformation, the protein has become the target of anticancer therapies. Quite a few LSD1 inhibitors, including 2-PCPA, GSK-2879552, IMG-7289, INCB059872 and CC-90011, have been reported to date as currently undergoing clinical assessment, against solid tumours as small lung cancer cells (SCLC) but also against leukemias as acute myeloid leukemia (AML) [34]. While more and more is known about LSD1 with regard to cancer biology, numerous studies reveal that the physiological effects of demethylase differ from those of pathological conditions.…”

Section: Discussionmentioning

confidence: 99%

The Role of Lysine-Specific Demethylase 1 (LSD1) in Shaping the Endothelial Inflammatory Response

Wojtala

Rybaczek

Wielgus

et al. 2021

Cell Physiol Biochem

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Background/Aims: Inflammation is the body’s natural response to stress in the broadest sense. The regulatory mechanisms that control this process, some of which are still unclear, are needed to balance the immune response, but also when insufficient, can cause immunodeficiency resulting in infection, cancer, neurodegeneration or other serious disorders. In this study, we focused on defining the role of lysine-specific demethylase 1 (LSD1), an enzyme involved in modulating the methylation state of lysine, including histone and non-histone proteins, in shaping the inflammatory profile of endothelial cells. Methods: To determine the role of LSD1 in the inflammatory response of ECs, cells were stimulated with lipopolysaccharide (100 ng/ml LPS) in the presence and absence of an LSD1 inhibitor (2-PCPA). A transcription model of LSD1 deficient cells (HMEC-1 LSD1 KD) obtained by lentiviral shRNA transduction was also used. The indicated cellular models were analyzed by gene profiling, monitoring of p65 shuttling by Western blotting and immunofluorescence staining. Also chromatin immunoprecipitation (ChIP) was performed to identify the interactions between selected: IL-6/p65 and LSD1. Results: Analysis of both experimental models revealed an altered inflammatory response following both LSD1 inhibition and LSD1 silencing. We observed decreased U-937 monocytes recruitment to LPS-activated endothelial cells and decreased extracellular secretion of many proinflammatory cytokines, also confirmed at the transcript level by RT-qPCR. Monitoring of the LPS-induced p65 translocation revealed inhibition of the NF-κB subunit in LSD1 KD vs nonT as well as due to pretreatment of 2-PCPA cells. Gene profiling performed with RNA microarrays confirmed the obtained biochemical data at the transcript level. Conclusion: In conclusion, the conducted studies showed a proinflammatory profile of LSD1 activity in endothelial cells, revealed by the inhibition of the enzyme activity and confirmed at the transcriptional level by the inhibition of its expression. Although we found significant changes in the modification of interactions between monocytes and endothelial cells as well as in cytokine/chemokine release and expression that were consistent with the altered NF-κB-p65 translocation into the nucleus, we did not identify a direct interaction between LSD1 and the transcription factor. Our finding may have important implications for prevention of cardiovascular diseases at their first stage - activation of the endothelium as well as for tumor cell biology, providing evidence for the use of LSD1 inhibitors to reduce the inflammatory response, which enhances tumor tissue remodeling, angiogenesis and metastasis.

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“…The essential role of Kdm1a in hematopoiesis has been shown in vitro 31 , 32 and in vivo 33 , 34 . As such, understanding the molecular mechanisms underpinning the action of Kdm1a are currently being investigated to find specific inhibitors that could be harnessed as a therapeutic strategy in cancer 35 . According to our bioinformatic analysis of single cell-RNAseq, kdm1a was not detected in hematopoietic cells of the zebrafish regenerating tailfin.…”

Section: Discussionmentioning

confidence: 99%

Nuclear S-nitrosylation impacts tissue regeneration in zebrafish

et al. 2021

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Despite the importance of nitric oxide signaling in multiple biological processes, its role in tissue regeneration remains largely unexplored. Here, we provide evidence that inducible nitric oxide synthase (iNos) translocates to the nucleus during zebrafish tailfin regeneration and is associated with alterations in the nuclear S-nitrosylated proteome. iNos inhibitors or nitric oxide scavengers reduce protein S-nitrosylation and impair tailfin regeneration. Liquid chromatography/tandem mass spectrometry reveals an increase of up to 11-fold in the number of S-nitrosylated proteins during regeneration. Among these, Kdm1a, a well-known epigenetic modifier, is S-nitrosylated on Cys334. This alters Kdm1a binding to the CoRest complex, thus impairing its H3K4 demethylase activity, which is a response specific to the endothelial compartment. Rescue experiments show S-nitrosylation is essential for tailfin regeneration, and we identify downstream endothelial targets of Kdm1a S-nitrosylation. In this work, we define S-nitrosylation as an essential post-translational modification in tissue regeneration.

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Annual review of LSD1/KDM1A inhibitors in 2020

Cited by 27 publications

References 94 publications

Inhibiting LSD1 suppresses coronavirus-induced inflammation but spares innate antiviral activity

Inhibiting LSD1 suppresses coronavirus-induced inflammation but spares innate antiviral activity

The Role of Lysine-Specific Demethylase 1 (LSD1) in Shaping the Endothelial Inflammatory Response

Nuclear S-nitrosylation impacts tissue regeneration in zebrafish

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