Pharmacological and transcriptional inhibition of the G9a histone methyltransferase suppresses proliferation and modulates redox homeostasis in human microvascular endothelial cells

Wojtala, Martyna; Macierzyńska-Piotrowska, Ewa; Rybaczek, Dorota; Pirola, Luciano; Balcerczyk, Aneta

doi:10.1016/j.phrs.2017.10.014

Cited by 24 publications

(18 citation statements)

References 39 publications

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“…In ECs, PHF8 maintained E2F4 expression by demethylating H3K9me2 at the E2F4 transcriptional start site to facilitate endothelial cell proliferation, survival, and the capacity for migration and development of capillary-like structures [120]. G9a is the methyltransferase that targets H3K9, and inhibition of G9a activity by BIX-01294 or knockdown by shRNA attenuates the proliferation of human microvascular ECs, and arresting them in the G1 phase of the cell cycle by regulating the phosphorylation of CHK1 [121]. In addition, histone methyltransferase MLL contributes to endothelial-cell sprout formation by regulating HoxA9 and EphB4 expression [122].…”

Section: Histone Methylation In Endothelial Cell Dysfunctionmentioning

confidence: 99%

Histone methylation and vascular biology

Wei

Zhu

et al. 2020

Clin Epigenet

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The vasculature not only transports oxygenated blood, metabolites, and waste products but also serves as a conduit for hormonal communication between distant tissues. Therefore, it is important to maintain homeostasis within the vasculature. Recent studies have greatly expanded our understanding of the regulation of vasculature development and vascular-related diseases at the epigenetic level, including by protein posttranslational modifications, DNA methylation, and noncoding RNAs. Integrating epigenetic mechanisms into the pathophysiologic conceptualization of complex and multifactorial vascular-related diseases may provide promising therapeutic approaches. Several reviews have presented detailed discussions of epigenetic mechanisms not including histone methylation in vascular biology. In this review, we primarily discuss histone methylation in vascular development and maturity, and in vascular diseases.

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Section: Histone Methylation In Endothelial Cell Dysfunctionmentioning

confidence: 99%

Histone methylation and vascular biology

Wei

Zhu

et al. 2020

Clin Epigenet

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“…Histone methyltransferase (HMT) inhibition directly affected the proliferation of ECs by suppressing cell cycle progression in the G 0 /G 1 phase [83]. Cell cycle arrest in the G 1 phase was also observed by inhibiting the HMT G9a, by either BIX-01294 or chaetocin pharmacological inhibitors, and shRNA knockdown [84]. Histone methylation was also shown to be an important mark of angiogenesis, as knockdown of HMT DOT1L (a histone H3K79 methyltransferase) in HUVECs resulted in decreased cell viability, tube and capillary sprout formation [85].…”

Section: Histone Posttranslational Modificationsmentioning

confidence: 99%

The Epigenetic Profile of Tumor Endothelial Cells. Effects of Combined Therapy with Antiangiogenic and Epigenetic Drugs on Cancer Progression

Ciesielski

Biesiekierska

Panthu

et al. 2020

IJMS

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Tumors require a constant supply of nutrients to grow which are provided through tumor blood vessels. To metastasize, tumors need a route to enter circulation, that route is also provided by tumor blood vessels. Thus, angiogenesis is necessary for both tumor progression and metastasis. Angiogenesis is tightly regulated by a balance of angiogenic and antiangiogenic factors. Angiogenic factors of the vascular endothelial growth factor (VEGF) family lead to the activation of endothelial cells, proliferation, and neovascularization. Significant VEGF-A upregulation is commonly observed in cancer cells, also due to hypoxic conditions, and activates endothelial cells (ECs) by paracrine signaling stimulating cell migration and proliferation, resulting in tumor-dependent angiogenesis. Conversely, antiangiogenic factors inhibit angiogenesis by suppressing ECs activation. One of the best-known anti-angiogenic factors is thrombospondin-1 (TSP-1). In pathological angiogenesis, the balance shifts towards the proangiogenic factors and an angiogenic switch that promotes tumor angiogenesis. Here, we review the current literature supporting the notion of the existence of two different endothelial lineages: normal endothelial cells (NECs), representing the physiological form of vascular endothelium, and tumor endothelial cells (TECs), which are strongly promoted by the tumor microenvironment and are biologically different from NECs. The angiogenic switch would be also important for the explanation of the differences between NECs and TECs, as angiogenic factors, cytokines and growth factors secreted into the tumor microenvironment may cause genetic instability. In this review, we focus on the epigenetic differences between the two endothelial lineages, which provide a possible window for pharmacological targeting of TECs.Int. J. Mol. Sci. 2020, 21, 2606 2 of 22 organ" spread over an area of approximately 7 m 2 that controls: (i) the flow of blood, (ii) organism nutrition by the passage of metabolites and gases exchange, (iii) immunity by circulating immune cells and antibodies, as well as (iv) trafficking of leukocytes [2][3][4]. Moreover, endothelial cells are involved in several physiological processes including (v) angiogenesis, (vi) blood coagulation and fibrinolysis, (vii) vasomotor and blood pressure regulation, and (viii) inflammatory reactions, which are conditioned by a multitude of synthesized and released hormonal and chemical mediators, including vascular endothelial growth factor (VEGF), nitric oxide (NO • ), or prostaglandin E2 [5][6][7].Dysfunction of the endothelium results in a number of disorders. In tumors, endothelial cells due to chronic stimulation by growth factors and hypoxia, change their phenotype into tumor endothelial cells (TECs), which results in abnormalities in tumor blood vessel morphology. TECs are fragile and leaky as compared to normal vessels, that in consequence alters blood flow. These abnormalities in the tumor endothelium contribute to tumor growth and metastasis [8,9]. Thus, a detailed under...

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“…The histone methyltransferase (HMTase) G9a, an epigenetic enzyme w ubiquitously expressed in somatic cells, contributes to the development and progression of various cancers [9][10][11][12][13]. G9a regulates the transcription of multiple genes by primarily catalyzing the dimethylation of histone H3 lysine 9 (H3K9me2) [13] and induces changes in cellular redox homeostasis, leading to a decrease in reactive oxygen species (ROS) production [14]. The G9a protein is accumulated under hypoxic conditions, without an alteration in the levels of G9a transcripts, leading to the epigenetic silencing of specific genes in cancer cells [15,16].…”

Section: Introductionmentioning

confidence: 99%

“…High levels of G9 expression are associated with unfavorable clinical outcomes, including disease progression, metastasis, development of stem cell-like characteristics, resistance to treatment, and poor survival [17,18]. Inhibition of G9a suppresses cell proliferation and modulates redox homeostasis, with an increase in ROS generation [14]. It has been shown that G9a inhibition induces cancer cell death via intracellular ROS production [19].…”

Section: Introductionmentioning

confidence: 99%

PERK/NRF2 and autophagy form a resistance mechanism against G9a inhibition in leukemia stem cells

Jang

Eom

Jeung

et al. 2020

J Exp Clin Cancer Res

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Background: The histone methyltransferase G9a has recently been identified as a potential target for epigenetic therapy of acute myeloid leukemia (AML). However, the effect of G9a inhibition on leukemia stem cells (LSCs), which are responsible for AML drug resistance and recurrence, is unclear. In this study, we investigated the underlying mechanisms of the LSC resistance to G9a inhibition. Methods:We evaluated the effects of G9a inhibition on the unfolded protein response and autophagy in AML and LSC-like cell lines and in primary CD34 + CD38 − leukemic blasts from patients with AML and investigated the underlying mechanisms. The effects of treatment on cells were evaluated by flow cytometry, western blotting, confocal microscopy, reactive oxygen species (ROS) production assay. Results: The G9a inhibitor BIX-01294 effectively induced apoptosis in AML cell lines; however, the effect was limited in KG1 LSC-like cells. BIX-01294 treatment or siRNA-mediated G9a knockdown led to the activation of the PERK/ NRF2 pathway and HO-1 upregulation in KG1 cells. Phosphorylation of p38 and intracellular generation of reactive oxygen species (ROS) were suppressed. Pharmacological or siRNA-mediated inhibition of the PERK/NRF2 pathway synergistically enhanced BIX-01294-induced apoptosis, with suppressed HO-1 expression, increased p38 phosphorylation, and elevated ROS generation, indicating that activated PERK/NRF2 signaling suppressed ROS-induced apoptosis in KG1 cells. By contrast, cotreatment of normal hematopoietic stem cells with BIX-01294 and a PERK inhibitor had no significant proapoptotic effect. Additionally, G9a inhibition induced autophagy flux in KG1 cells, while autophagy inhibitors significantly increased the BIX-01294-induced apoptosis. This prosurvival autophagy was not abrogated by PERK/NRF2 inhibition.Conclusions: PERK/NRF2 signaling plays a key role in protecting LSCs against ROS-induced apoptosis, thus conferring resistance to G9a inhibitors. Treatment with PERK/NRF2 or autophagy inhibitors could overcome resistance to G9a inhibition and eliminate LSCs, suggesting the potential clinical utility of these unique targeted therapies against AML.

show abstract

Pharmacological and transcriptional inhibition of the G9a histone methyltransferase suppresses proliferation and modulates redox homeostasis in human microvascular endothelial cells

Cited by 24 publications

References 39 publications

Histone methylation and vascular biology

Histone methylation and vascular biology

The Epigenetic Profile of Tumor Endothelial Cells. Effects of Combined Therapy with Antiangiogenic and Epigenetic Drugs on Cancer Progression

PERK/NRF2 and autophagy form a resistance mechanism against G9a inhibition in leukemia stem cells

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