作者: Kundu, Supratik ; Xia, Min ; Jiang, Rong ; Li, Shao ; Yang, XueWei ; Guan, Rongxiao ; Ntim, Michael ; Wang, Bin ; Wang, Ying ; Lu, Jincheng ; Chen, Defang

Tat-interacting protein 60 (TIP60) as nuclear receptors (NRs) coregulator, acts as a tumor suppressor and also has promising therapeutic potential to target Alzheimer's disease. Stress has been implicated in many psychiatric disorders, and these disorders are characterized by impairments in cognitive function. Until now, there are no experimental data available on the regulatory effect of TIP60 in acute stress and depression. There is also no definitive explanation on which specific modulation of target gene expression is achieved by TIP60. Here, we identify TIP60 as a novel positive regulator in response to acute restraint stress (ARS) and a potentially effective target of antidepressants. Firstly, we discovered increased hippocampal TIP60 expressions in the ARS model. Furthermore, using the TIP60 inhibitor, MG149, we proved that TIP60 function correlates with behavioral and synaptic activation in the two-hour ARS. Secondly, the lentivirus vector (LV)-TIP60^{overexpression (OE)} was injected into the hippocampus prior to the chronic restraint stress (CRS) experiments and it was found that over-expressed TIP60 compensates for TIP60 decrease and improves depression index in CRS. Thirdly, through the intervention of TIP60 expression in vitro, we established the genetic regulation of TIP60 on synaptic proteins, confirmed the TIP60 function as a specific coactivator for PPARγ and found that the PPARγ-mediated TIP60 function modulates transcriptional activation of synaptic proteins. Finally, the LV-TIP60^OE and PPARγ antagonist, GW9662, were both administered in the CRS model and the data indicated that blocking PPARγ significantly weakened the protective effect of TIP60 against the CRS-induced depression. Conclusively, these findings together support TIP60 as a novel positive factor in response to acute stress and interacts with PPARγ to modulate the pathological mechanism of CRS-induced depression.

Scientific Reports

KAT8 compound inhibition inhibits the initial steps of PINK1-dependant mitophagy

Article

作者: Plun-Favreau, Helene ; Esteras, Noemi ; Soutar, Marc P M ; de Talhouët, Capucine ; O'Callaghan, Benjamin

AbstractIt has recently been shown that KAT8, a genome-wide association study candidate risk gene for Parkinson’s Disease, is involved in PINK1/Parkin-dependant mitophagy. The KAT8 gene encodes a lysine acetyltransferase and represents the catalytically active subunit of the non-specific lethal epigenetic remodelling complex. In the current study, we show that contrary to KAT5 inhibition, dual inhibition of KAT5 and KAT8 via the MG149 compound inhibits the initial steps of the PINK1-dependant mitophagy process. More specifically, our study shows that following mitochondrial depolarisation induced by mitochondrial toxins, MG149 treatment inhibits PINK1-dependant mitophagy initiation by impairing PINK1 activation, and subsequent phosphorylation of Parkin and ubiquitin. While this inhibitory effect of MG149 on PINK1-activation is potent, MG149 treatment in the absence of mitochondrial toxins is sufficient to depolarise the mitochondrial membrane, recruit PINK1 and promote partial downstream recruitment of the autophagy receptor p62, leading to an increase in mitochondrial delivery to the lysosomes. Altogether, our study provides additional support for KAT8 as a regulator of mitophagy and autophagy processes.

International Journal of Molecular Sciences

Fluoride Alters Gene Expression via Histone H3K27 Acetylation in Ameloblast-like LS8 Cells

Article

作者: Yamashita, Shohei ; Everett, Eric T. ; Shindo, Satoru ; Mendonca, Melanie ; Brueckner, Susanne ; Gill Dhillon, Navi ; Chang, Chang-Sheng Sam ; Kuriki, Nanako ; Kitamura, Eiko ; Suzuki, Maiko ; Kawai, Toshihisa ; Okamoto, Motoki ; Bartlett, John D. ; Fujiwara, Natsumi ; Cooley, Marion A.

Excessive fluoride ingestion during tooth development can cause dental fluorosis. Previously, we reported that fluoride activates histone acetyltransferase (HAT) to acetylate p53, promoting fluoride toxicity in mouse ameloblast-like LS8 cells. However, the roles of HAT and histone acetylation status in fluoride-mediated gene expression remain unidentified. Here, we demonstrate that fluoride-mediated histone modification causes gene expression alterations in LS8 cells. LS8 cells were treated with or without fluoride followed by ChIP-Seq analysis of H3K27ac. Genes were identified by differential H3K27ac peaks within ±1 kb from transcription start sites. The levels of mRNA of identified genes were assessed using rea-time PCR (qPCR). Fluoride increased H3K27ac peaks associated with Bax, p21, and Mdm2 genes and upregulated their mRNA levels. Fluoride decreased H3K27ac peaks and p53, Bad, and Bcl2 had suppressed transcription. HAT inhibitors (Anacardic acid or MG149) suppressed fluoride-induced mRNA of p21 and Mdm2, while fluoride and the histone deacetylase (HDAC) inhibitor sodium butyrate increased Bad and Bcl2 expression above that of fluoride treatment alone. To our knowledge, this is the first study that demonstrates epigenetic regulation via fluoride treatment via H3 acetylation. Further investigation is required to elucidate epigenetic mechanisms of fluoride toxicity in enamel development.

项与 MG-149 相关的新闻（医药）

2024-04-06

·今日头条

抑制肿瘤生长！中山大学最新发文：肿瘤治疗新策略

本文为转化医学网原创，转载请注明出处作者：Sophia 导读：膀胱癌（BC）是最常见的肿瘤之一，其特征是复发率高且缺乏靶向治疗。近日，中山大学武远众及康铁邦共同通讯在Advanced Science 在线发表题为“Targeting the KAT8/YEATS4 Axis Represses Tumor Growth and Increases Cisplatin Sensitivity in Bladder Cancer”的研究论文，我们的研究表明，YEATS4 翻译后修饰的失调可能是 BC 中 YEATS4 上调的主要原因。因此，通过靶向 KAT8/YEATS4 轴来抑制 YEATS4 乙酰化可能是 BC 患者的一种有前途的治疗干预措施。 https://onlinelibrary.wiley.com/doi/10.1002/advs.202310146 研究背景 01 膀胱癌（BC）是全球最常见的恶性肿瘤之一。膀胱癌的发病率和死亡率逐年增加。尽管 BC 标本中基因突变（如 FGFR3 和 p53）的鉴定以及染色体改变揭示了 BC 的发展，但仍缺乏特异性的靶向治疗。基于顺铂（DDP）的联合化疗已成为侵袭性或转移性 BC 患者的重要辅助疗法。然而，大多数 BC 患者会逐渐出现 DDP 耐药。因此，亟需确定BC的新治疗靶点。含有 YEATS 结构域的蛋白质具有保守的 YEATS 结构域，具有重要的生物学意义，因为它们最近被确定为组蛋白乙酰化的新读者。在人类中，有 4 种含有 YEATS 结构域的蛋白质，包括 AF9、ENL、YEATS4 和 YEATS2。特别是，ENL与对急性白血病发展至关重要的癌基因的反式激活有关。诱导 ENL 蛋白降解或靶向 ENL YEATS 结构域导致致癌基因的抑制和癌细胞活力的降低，表明 YEATS 蛋白可能是癌症治疗的潜在治疗靶点。 YEATS4，也称为 GAS41，最初被发现在胶质母细胞瘤中扩增。新兴研究表明，YEATS4 对细胞存活、细胞生长和 p53 通路调节至关重要。尽管意识到 YEATS4 在癌症中的关键作用，但由于对 YEATS4 在癌症中如何调节知之甚少，这种蛋白质的靶向策略仍然不可用。研究结果 02 本研究，我们使用 CRISPR-Cas9 文库筛选报告了含 YEATS 结构域的蛋白 4 （YEATS4）是 BC 细胞活力的重要基因，并且 HUWE1 是一种 E3 连接酶，负责 YEATS4 泛素化和蛋白酶体降解通过蛋白质稳定性调节剂筛选测定。 KAT8介导的YEATS4乙酰化损害了其与HUWE1的相互作用，从而阻止了其泛素化和降解。YEATS4 和 KAT8 的蛋白水平呈正相关，这两种蛋白的高水平与 BC 患者的总生存期较差有关。重要的是，用 KAT8 抑制剂 MG149 抑制 YEATS4 乙酰化可降低 YEATS4 乙酰化，降低细胞活力，并使 BC 细胞对顺铂治疗敏感。研究结果揭示了 KAT8/YEATS4 轴在 BC 细胞肿瘤生长和顺铂敏感性中的关键作用，有可能为 BC 患者提供一种新的治疗策略。研究结论 03 在这项研究中，我们发现 KAT8/YEATS4 轴对 BC 至关重要。具体来说，在 BC 细胞中，KAT8 介导的 YEATS4 乙酰化位点 K64、65 和 69 通过阻断其 HUWE1 依赖性降解来促进 YEATS4 的稳定，这反过来又有助于 DNA 修复和肿瘤生长，从而导致 DDP 耐药性。MG149 抑制 KAT8 抑制 YEATS4 乙酰化，导致 HUWE1 与 YEATS4 结合增加，从而促进 HUWE1 介导的 YEATS4 泛素化和蛋白酶体降解，从而减少 DNA 修复和肿瘤生长并增强 DDP 敏感性（图 8）。 BC中KAT8/YEATS4轴功能的拟议模型。 KAT8 药物的 YEATS4 乙酰化位点 K64、65 和 69 阻断 HUWE1 与 YEATS4 的结合，从而促进 YEATS4 稳定，从而促进 DNA 修复和肿瘤生长。MG149 抑制 KAT8 抑制 YEATS4 乙酰化，导致 HUWE1 与 YEATS4 结合增加和蛋白酶体降解，从而增强基因组不稳定性并抑制 BC 细胞生长。MG149 阻断 YEATS4 乙酰化可增加 DDP 敏感性并加速 BC 细胞死亡。参考资料： https://onlinelibrary.wiley.com/doi/10.1002/advs.202310146 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 上海｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！点击对应文字查看详情

蛋白降解靶向嵌合体

100 项与 MG-149 相关的药物交易

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