Kulka Linda Anna Michelle, Fangmann Pia-Victoria, Panfilova Diana, Olzscha Heidi
Medical Faculty, Institute of Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
Front Cell Dev Biol. 2020 Jun 3;8:425. doi: 10.3389/fcell.2020.00425. eCollection 2020.
Lysine acetylation is one of the major posttranslational modifications (PTM) in human cells and thus needs to be tightly regulated by the writers of this process, the histone acetyl transferases (HAT), and the erasers, the histone deacetylases (HDAC). Acetylation plays a crucial role in cell signaling, cell cycle control and in epigenetic regulation of gene expression. Bromodomain (BRD)-containing proteins are readers of the acetylation mark, enabling them to transduce the modification signal. HDAC inhibitors (HDACi) have been proven to be efficient in hematologic malignancies with four of them being approved by the FDA. However, the mechanisms by which HDACi exert their cytotoxicity are only partly resolved. It is likely that HDACi alter the acetylation pattern of cytoplasmic proteins, contributing to their anti-cancer potential. Recently, it has been demonstrated that various protein quality control (PQC) systems are involved in recognizing the altered acetylation pattern upon HDACi treatment. In particular, molecular chaperones, the ubiquitin proteasome system (UPS) and autophagy are able to sense the structurally changed proteins, providing additional targets. Recent clinical studies of novel HDACi have proven that proteins of the UPS may serve as biomarkers for stratifying patient groups under HDACi regimes. In addition, members of the PQC systems have been shown to modify the epigenetic readout of HDACi treated cells and alter proteostasis in the nucleus, thus contributing to changing gene expression profiles. Bromodomain (BRD)-containing proteins seem to play a potent role in transducing the signaling process initiating apoptosis, and many clinical trials are under way to test BRD inhibitors. Finally, it has been demonstrated that HDACi treatment leads to protein misfolding and aggregation, which may explain the effect of panobinostat, the latest FDA approved HDACi, in combination with the proteasome inhibitor bortezomib in multiple myeloma. Therefore, proteins of these PQC systems provide valuable targets for precision medicine in cancer. In this review, we give an overview of the impact of HDACi treatment on PQC systems and their implications for malignant disease. We exemplify the development of novel HDACi and how affected proteins belonging to PQC can be used to determine molecular signatures and utilized in precision medicine.
赖氨酸乙酰化是人类细胞中主要的翻译后修饰（PTM）之一，因此需要由该过程的“书写者”——组蛋白乙酰转移酶（HAT）和“擦除者”——组蛋白脱乙酰酶（HDAC）进行严格调控。乙酰化在细胞信号传导、细胞周期控制以及基因表达的表观遗传调控中起着至关重要的作用。含溴结构域（BRD）的蛋白质是乙酰化标记的“读取者”，使它们能够转导修饰信号。HDAC抑制剂（HDACi）已被证明在血液系统恶性肿瘤中有效，其中四种已获得美国食品药品监督管理局（FDA）批准。然而，HDACi发挥细胞毒性的机制仅部分得到解决。HDACi可能会改变细胞质蛋白的乙酰化模式，这有助于其抗癌潜力。最近，已经证明各种蛋白质质量控制（PQC）系统参与识别HDACi处理后改变的乙酰化模式。特别是，分子伴侣、泛素蛋白酶体系统（UPS）和自噬能够感知结构发生变化的蛋白质，提供了额外的靶点。新型HDACi的近期临床研究证明，UPS的蛋白质可能作为在HDACi治疗方案下对患者群体进行分层的生物标志物。此外，PQC系统的成员已被证明可以改变HDACi处理细胞的表观遗传读数，并改变细胞核中的蛋白质稳态，从而有助于改变基因表达谱。含溴结构域（BRD）的蛋白质似乎在转导启动细胞凋亡的信号传导过程中发挥重要作用，并且许多临床试验正在进行以测试BRD抑制剂。最后，已经证明HDACi处理会导致蛋白质错误折叠和聚集，这可能解释了最新获得FDA批准的HDACi帕比司他与蛋白酶体抑制剂硼替佐米联合用于多发性骨髓瘤的效果。因此，这些PQC系统的蛋白质为癌症精准医学提供了有价值的靶点。在本综述中，我们概述了HDACi处理对PQC系统的影响及其对恶性疾病的影响。我们举例说明了新型HDACi的开发以及属于PQC的受影响蛋白质如何用于确定分子特征并应用于精准医学。
