Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

Cuyàs, Elisabet; Verdura, Sara; Llorach-Parés, Laura; Fernández-Arroyo, Salvador; Luciano-Mateo, Fedra; Cabré, Noemí; Štursa, Jan; Werner, Lukáš; Martín-Castillo, Begoña; Viollet, Benoı̂t; Neužil, Jiřı́; Joven, Jorge; Nonell-Canals, Alfons; Sánchez-Martínez, Melchor; Menendez, Javier A.

doi:10.1111/acel.12772

Cited by 60 publications

(54 citation statements)

References 66 publications

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“…Recently, KDM6A was identified as the molecular target of metformin. Metformin is an FDA-approved drug for the treatment of diabetes; it inhibits the histone demethylase activity of KDM6A to increase the global level of H3K27me3 histone modifications (43). Thus, in the context of this study, metformin could be viewed Figure 4.…”

Section: Discussionmentioning

confidence: 99%

The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity

Itoh¹,

Golden²,

Itoh³

et al. 2019

Journal of Clinical Investigation

111

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This sex difference of KDM6A gene expression was confirmed in human naive CD4 + T cells (Figure 1E). That other genes thought to escape X inactivation do not appear when comparing female versus male CD4 + T cell data sets may be due to a variety of factors, such as the tissue type, cell type, or hormonal status (28). We then used the FCG mouse model (20, 21), which allows comparison of XX and XY‾ mice of the same gonadal sex (Y‾ denotes lack of the testis-determining Sry gene on the Y chromosome). In addition, XX and XY‾ gonadal females were ovariectomized to remove activational effects of ovarian hormones. In autoantigen-stimulated CD4 + T cells from C57BL/6J and SJL mice, there was higher expression of Kdm6a and Kdm5c in XX compared with XY‾ mice (Figure 1, C and D, and Supplemental Figure 1, B and C). In contrast, other genes thought to escape X inactivation, namely, Ddx3x, Eif2s3x, Uba1, and Usp9x, were not differentially expressed between XX and XY‾ CD4 + T cells (Supplemental Figure 1, B and C). cKO mice are protected from EAE. Since Kdm6a was the most differentially expressed X escapee, we next investigated to determine whether Kdm6a expression in CD4 + T cells influences autoimmune disease. We crossed mice containing homozygous floxed Kdm6a alleles with mice expressing Cre under the CD4 promoter to produce a conditional KO of Kdm6a only in CD4 + T cells (cKO). Deletion of Kdm6a in CD4 + T cells was confirmed with genomic PCR (Figure 2A). As expected, expression of Kdm6a was decreased in cKO compared with WT in the CD4 + T cells from EAE mice that were stimulated with autoantigen (Figure 2B, FDR = 0.07). To examine the functional significance of Kdm6a expression in CD4 + T cells on disease, active EAE was induced in female cKO and WT (littermate controls; CD4-Cre negative) mice (Figure 2C). EAE clinical scores of cKO mice were lower than those in WT mice (P < 0.0001), demonstrating that deletion of Kdm6a in CD4 + T cells was protective. This protective effect of Kdm6a deletion in CD4 + T cells was further confirmed with 3 additional EAE experiments, including 1 experiment in males (Table 1). Together, these data show that the presence of Kdm6a in CD4 + T cells is disease promoting in the classic CD4 + T cellmediated autoimmune disease EAE. Consistent with an amelioration of clinical EAE scores, immunohistochemistry of spinal cord white matter showed a reduction of CD3 + T lymphocytes and Iba1 + globoid macrophages in cKO compared with WT mice (Figure 2, D and E). Assessment of neurodegeneration in spinal cord white matter showed reduction of βAPP + injured axons and an increase in

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Section: Discussionmentioning

confidence: 99%

The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity

Itoh¹,

Golden²,

Itoh³

et al. 2019

Journal of Clinical Investigation

111

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“…This rather pleiotropic effect of metformin led to unspecific increase in mitochondrial ROS generation, suggesting that metformin does not bind to any specific site on respiratory chain enzymes. Yet another line of evidence against mGPDH as metformin target comes from bioinformatics screen for potential metformin binders, which identified several interesting candidates, such as dynamin‐1, arginase‐2 or pyruvate kinase, but failed to identify either mGPDH or any subunit of complex I …”

Section: Mitochondrial Targets Of Metforminmentioning

confidence: 99%

“…Yet another line of evidence against mGPDH as metformin target comes from bioinformatics screen for potential metformin binders, which identified several interesting candidates, such as dynamin-1, arginase-2 or pyruvate kinase, but failed to identify either mGPDH or any subunit of complex I. 46 It is questionable, if mGPDH inhibition may represent relevant mechanism of lowering endogenous glucose, since mGPDH content in liver is very low and MAS represents the major NADH shuttling mechanism. 43 Definitely, further studies will be required to prove that GPS inhibition may lead to lowering of endogenous glucose production.…”

Section: Mitochondrial Glycerophosphate Dehydrogenasementioning

confidence: 99%

Mitochondrial targets of metformin—Are they physiologically relevant?

et al. 2019

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Metformin is the most widely prescribed treatment of hyperglycemia and type II diabetes since 1970s. During the last 15 years, its popularity increased due to epidemiological evidence, that metformin administration reduces incidence of cancer. However, despite the ongoing effort of many researchers, the molecular mechanisms underlying antihyperglycemic or antineoplastic action of metformin remain elusive. Most frequently, metformin is associated with modulation of mitochondrial metabolism leading to lowering of blood glucose or activation of antitumorigenic pathways. Here we review the reported effects of metformin on mitochondrial metabolism and their potential relevance as effective molecular targets with beneficial therapeutic outcome.

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“…Metformin has been proposed to exert indirect pleiotropy on core metabolic hallmarks of aging such as the insulin/IGF-1 and AMPK/mTOR signaling pathways ( 4 ) downstream of its primary inhibitory action on mitochondrial respiratory complex I. Alternatively, but not mutually exclusive, its capacity to operate as a poly-therapeutic anti-aging agent might involve the direct targeting of the biologic machinery of aging per se . A systematic chemoinformatics approach established to computationally predict metformin targets recently revealed that the salutary effects of metformin on human cellular aging might involve its direct binding to core chromatin modifiers of the aging epigenome ( 7 , 8 ), such as the H3K27me3 demethylase KDM6A/UTX ( 9 – 11 ). The ability of metformin to directly interact with TGF-β1, thereby blocking its binding to TβRII and resulting in impaired downstream signaling ( 12 ), is another example of how metformin might exert pleiotropic effects on numerous (TGF-β1 hyperfunction-associated) aging diseases such as organ fibrosis and cancer, without necessarily involving changes in cellular bioenergetics.…”

Section: Introductionmentioning

confidence: 99%

Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation

et al. 2018

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Metformin has been proposed to operate as an agonist of SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that mimics most of the metabolic responses to calorie restriction. Herein, we present an in silico analysis focusing on the molecular docking and dynamic simulation of the putative interactions between metformin and SIRT1. Using eight different crystal structures of human SIRT1 protein, our computational approach was able to delineate the putative binding modes of metformin to several pockets inside and outside the central deacetylase catalytic domain. First, metformin was predicted to interact with the very same allosteric site occupied by resveratrol and other sirtuin-activating compounds (STATCs) at the amino-terminal activation domain of SIRT1. Second, metformin was predicted to interact with the NAD+ binding site in a manner slightly different to that of SIRT1 inhibitors containing an indole ring. Third, metformin was predicted to interact with the C-terminal regulatory segment of SIRT1 bound to the NAD+ hydrolysis product ADP-ribose, a “C-pocket”-related mechanism that appears to be essential for mechanism-based activation of SIRT1. Enzymatic assays confirmed that the net biochemical effect of metformin and other biguanides such as a phenformin was to improve the catalytic efficiency of SIRT1 operating in conditions of low NAD+ in vitro. Forthcoming studies should confirm the mechanistic relevance of our computational insights into how the putative binding modes of metformin to SIRT1 could explain its ability to operate as a direct SIRT1-activating compound. These findings might have important implications for understanding how metformin might confer health benefits via maintenance of SIRT1 activity during the aging process when NAD+ levels decline.

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Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

Cited by 60 publications

References 66 publications

The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity

The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity

Mitochondrial targets of metformin—Are they physiologically relevant?

Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation

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