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  • just like On the other hand G a GLP

    2022-08-04

    On the other hand, G9a/GLP could also alter neuronal function without directly altering the transcription level of particular plasticity-related protein: the consolidation of early-LTP to late-LTP, as well as the reversal of mGluR-LTD by G9a/GLP inhibition required PKMζ translation and its downstream pathway (). Application of BIX or UNC suppressed the DHPG-induced decrease in PKMζ protein expression without changing PKMζ mRNA levels, suggesting that the G9a/GLP regulation of PKMζ expression was probably indirect.
    Introduction Proliferation of eukaryotic cells is regulated by multiple extracellular stimuli (immune signals, cytokines, reactive oxygen species), that relay signals to the intracellular just like machinery, orchestrated by cyclins, cyclin-dependent kinases, Rb, p21, p27 and transcription factors (e.g. E2F), resulting in the activation or repression of proliferation. Control of cell proliferation generally occurs during the first gap phase (G1) of the cell division cycle. The decision to enter S phase from G1 is an irreversible point that, in the absence of major stress such as DNA damage which may subsequently block the cells in the second gap phase (G2), commits the cell towards completion of the cell cycle and cell division. Recent studies have underscored the importance of the interaction between proteins of the cell cycle machinery and epigenetic mechanisms in controlling of cell proliferation [1], [2]. A large body of evidence indicates a role of DNA methylation and post-translational covalent histone modifications, including acetylation, methylation, phosphorylation and ubiquitination, in the regulation of the cell cycle through the modulation of chromatin structure and transcriptional processes [3], [4], [5], [6], [7]. Dysregulation of cellular proliferation is a hallmark of multiple pathologies, including vascular proliferation disorders (atherosclerosis, diabetic vascular complications, restenosis) and cancer. Detailed analysis of cancer cell biology underscored the involvement of the euchromatic histone lysine methyltransferase 2 (also known as G9a HMT), an HMT that methylates histone H3 on lysines 9 and 27 to repress gene expression [8], and is a central enzyme to control cell proliferation, senescence and replication. The cell cycle machinery is regulated by G9a HMT via its recruitment on the repressive transcription complexes UHRF1, Gfi1, CDP/Cut and WIZ to the promoter of p21Cip/Waf1 [9], [10], [11]. The transcriptional activity of G9a HMT is just like not purely repressive, as the enzyme can also act as a co-activator for nuclear receptors, inducing cellular differentiation [12], [13], colorectal [14] and ovarian [15], cancers, gliomas [16] and oesophageal squamous cell carcinoma [17], suggesting that G9a HMT inhibition can be an attractive target to inhibit tumor growth [18]. Interactions between cancer cells and newly formed blood vessels are necessary to support tumor growth, with cytokines and chemokines released by tumors being able to significantly accelerate endothelial cell proliferation and stimulate tumor-induced angiogenesis to secure proper delivery of oxygen and nutrients needed for tumor progression. In this context, the role of G9a HMT in the promotion of endothelial cells proliferation is unexplored. Here, we studied the role of G9a HMT in the regulation of human microvascular endothelial cells (HMEC-1) proliferation using structurally unrelated inhibitors directed to G9a HMT and shRNA targeting of G9a HMT gene expression. We analyzed the consequences of pharmacological and transcriptional attenuation of G9a HMT activity on the cell cycle machinery and redox homeostasis. Consistent with studies performed on tumor cells, we found that G9a HMT negatively regulates endothelial cells proliferation i) via a Chk1-dependent mechanism, and ii) via overexpression of key checkpoint genes Rb and p21. Also, changes in the redox homeostasis of cells, leading to decreased reactive oxygen species production and a parallel enhancement of the antioxidant potential of cells was observed.