LSD1 demethylates HIF1α to inhibit hydroxylation and ubiquitin-mediated degradation in tumor angiogenesis

Lee, J. Y.; Park, J. H.; Choi, Hyung Jong; Won, Hee-Young; Joo, Hyeong-Seok; Shin, Dong‐Hui; Park, M. K.; Han, Bitnara; Kim, Kwang Pyo; Lee, Tae Jin; Croce, Carlo M.; Kong, Gu

doi:10.1038/onc.2017.158

Cited by 102 publications

(99 citation statements)

References 42 publications

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“…SET7/9-mediated monomethylation of HIF-1α at K32 was later confirmed by Kim et al in vitro and in human cervical carcinoma HeLa cells [46]. SET7/9 also catalyzes dimethylation of HIF-1α at K391 in HEK293T cells [38]. However, these two recent studies showed that SET7/9-mediated HIF-1α methylation decreases HIF-1α protein levels through increasing VHL-HIF-1α interaction and HIF-1α ubiquitination, thereby inhibiting HIF-1 transcriptional activity in transfected cells [38, 46].…”

Section: Regulation Of Hif Transcriptional Activity By Epigenetic Wrimentioning

confidence: 95%

“…However, ARD1 fails to acetylate HIF-1α in vitro [36, 37]. It was recently suggested that prolyl hydroxylation and K391 methylation are prerequisite for ARD1-mediated K532 acetylation of HIF-1α [38]. …”

Section: Regulation Of Hif Transcriptional Activity By Epigenetic Wrimentioning

confidence: 99%

“…SET7/9 also catalyzes dimethylation of HIF-1α at K391 in HEK293T cells [38]. However, these two recent studies showed that SET7/9-mediated HIF-1α methylation decreases HIF-1α protein levels through increasing VHL-HIF-1α interaction and HIF-1α ubiquitination, thereby inhibiting HIF-1 transcriptional activity in transfected cells [38, 46]. Upregulated HIF-1α protein and the HIF-1 target genes Epo , Vegfa , and Slc2a1 are observed in knockin mice bearing mutant Hif1a K32A/K32A [46].…”

Section: Regulation Of Hif Transcriptional Activity By Epigenetic Wrimentioning

confidence: 99%

“…Unlike JMJD proteins, LSD1 indirectly promotes HIF-1 transcriptional activity through altering HIF-1α protein degradation machinery [38, 46, 82]. LSD1 counteracts SET7/9-induced methylation of HIF-1α at K32 and K391 and also inhibit PHD2-mediated prolyl hydroxylation of HIF-1α to decrease HIF-1α ubiquitination and protein degradation [38, 46]. In addition, LSD1 interacts with and demethylates RACK1, which attenuates RACK1 binding to HIF-1α [82].…”

Section: Regulation Of Hif Transcriptional Activity By Epigenetic Eramentioning

confidence: 99%

“…Consequently, inhibition of LSD1 by its inhibitors or small interfering RNAs enhances RACK1-mediated HIF-1α protein degradation [82]. LSD1 potentiates transcription of HIF-1-dependent VEGFA and glycolytic genes in human cancer cells, leading to increased tumor angiogenesis [38, 82]. Interestingly, the FAD levels are reduced during prolonged hypoxia, which diminishes the demethylase activity of LSD1 [82].…”

Section: Regulation Of Hif Transcriptional Activity By Epigenetic Eramentioning

confidence: 99%

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Epigenetic regulators: multifunctional proteins modulating hypoxia-inducible factor-α protein stability and activity

Luo

Wang

2017

Cell. Mol. Life Sci.

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The hypoxia-inducible factor (HIF) is a heterodimeric transcription factor governing a transcriptional program in response to reduced O2 availability in metazoans. It contributes to physiology and pathogenesis of many human diseases through its downstream target genes. Emerging studies have shown that the transcriptional activity of HIF is highly regulated at multiple levels and the epigenetic regulators are essential for HIF-mediated transactivation. In this review, we will discuss the comprehensive regulation of HIF transcriptional activity by different types of epigenetic regulators.

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Section: Regulation Of Hif Transcriptional Activity By Epigenetic Wrimentioning

confidence: 95%

Section: Regulation Of Hif Transcriptional Activity By Epigenetic Wrimentioning

confidence: 99%

Section: Regulation Of Hif Transcriptional Activity By Epigenetic Wrimentioning

confidence: 99%

Section: Regulation Of Hif Transcriptional Activity By Epigenetic Eramentioning

confidence: 99%

Section: Regulation Of Hif Transcriptional Activity By Epigenetic Eramentioning

confidence: 99%

See 3 more Smart Citations

Epigenetic regulators: multifunctional proteins modulating hypoxia-inducible factor-α protein stability and activity

Luo

Wang

2017

Cell. Mol. Life Sci.

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The catalytic domains of all human KDM5 JmjC demethylases catalyse N‐methyl arginine demethylation

et al. 2023

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The demethylation of N e -methyllysine residues on histones by Jumonji-C lysine demethylases (JmjC-KDMs) has been established. A subset of JmjC-KDMs has also been reported to have N ω -methylarginine residue demethylase (RDM) activity. Here, we describe biochemical screening studies, showing that the catalytic domains of all human KDM5s (KDM5A-KDM5D), KDM4E and, to a lesser extent, KDM4A/D, have both KDM and RDM activities with histone peptides. Ras GTPase-activating protein-binding protein 1 peptides were shown to be RDM substrates for KDM5C/D. No RDM activity was observed with KDM1A and the other JmjC-KDMs tested. The results highlight the potential of JmjC-KDMs to catalyse reactions other than N e -methyllysine demethylation. Although our study is limited to peptide fragments, the results should help guide biological studies investigating JmjC functions.

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Role of Lysine‐Specific Demethylase 1 in Metabolically Integrating Osteoclast Differentiation and Inflammatory Bone Resorption Through Hypoxia‐Inducible Factor 1α and E2F1

Doi

Murata

Ito

et al. 2022

Arthritis & Rheumatology

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Objective. Hypoxia occurs in tumors, infections, and sites of inflammation, such as in the affected joints of patients with rheumatoid arthritis (RA). It alleviates inflammatory responses and increases bone resorption in inflammatory arthritis by enhancing osteoclastogenesis. The mechanism by which the hypoxia response is linked to osteoclastogenesis and inflammatory bone resorption is unclear. This study was undertaken to evaluate whether the protein lysinespecific demethylase 1 (LSD1) metabolically integrates inflammatory osteoclastogenesis and bone resorption in a state of inflammatory arthritis.Methods. LSD1-specific inhibitors and gene silencing with small interfering RNAs were used to inhibit the expression of LSD1 in human osteoclast precursor cells derived from CD14-positive monocytes, with subsequent assessment by RNA-sequencing analysis. In experimental mouse models of arthritis, inflammatory osteolysis, or osteoporosis, features of accelerated bone loss and inflammatory osteolysis were analyzed. Furthermore, in blood samples from patients with RA, cis-acting expression quantitative trait loci (cis-eQTL) were analyzed for association with the expression of hypoxiainducible factor 1α (HIF-1α), and associations between HIF-1α allelic variants and extent of bone erosion were evaluated.Results. In human osteoclast precursor cells, RANKL induced the expression of LSD1 in a mechanistic target of rapamycin-dependent manner. Expression of LSD1 was higher in synovium from RA patients than in synovium from osteoarthritis patients. Inhibition of LSD1 in human osteoclast precursors suppressed osteoclast differentiation. Results of transcriptome analysis identified several LSD1-mediated hypoxia and cell-cycle pathways as key genetic pathways involved in human osteoclastogenesis. Furthermore, HIF-1α protein, which is rapidly degraded by the proteasome in a normoxic environment, was found to be expressed in RANKL-stimulated osteoclast precursor cells. Induction of LSD1 by RANKL stabilized the expression of HIF-1α protein, thereby promoting glycolysis, in conjunction with up-regulation of the transcription factor E2F1. Analyses of cis-eQTL revealed that higher HIF-1α expression was associated with increased bone erosion in patients with RA. Inhibition of LSD1 decreased pathologic bone resorption in mice, both in models of accelerated osteoporosis and models of arthritis and inflammatory osteolysis.Conclusion. LSD1 metabolically regulates osteoclastogenesis in an energy-demanding inflammatory environment. These findings provide potential new therapeutic strategies targeting osteoclasts in the management of inflammatory arthritis, including in patients with RA.

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LSD1 demethylates HIF1α to inhibit hydroxylation and ubiquitin-mediated degradation in tumor angiogenesis

Cited by 102 publications

References 42 publications

Epigenetic regulators: multifunctional proteins modulating hypoxia-inducible factor-α protein stability and activity

Epigenetic regulators: multifunctional proteins modulating hypoxia-inducible factor-α protein stability and activity

The catalytic domains of all human KDM5 JmjC demethylases catalyse N‐methyl arginine demethylation

Role of Lysine‐Specific Demethylase 1 in Metabolically Integrating Osteoclast Differentiation and Inflammatory Bone Resorption Through Hypoxia‐Inducible Factor 1α and E2F1

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