Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
J Nutr Biochem. 2020 Oct;84:108444. doi: 10.1016/j.jnutbio.2020.108444. Epub 2020 Jun 2.
Gallic acid (GA) is known to possess diverse biological activities, including anticancer. Histone deacetylase (HDACs) are controlled by tumor suppressor gene transcription and are overexpressed in various tumors, resulting in tumor development, progression and poor prognosis. This study aims to demonstrate the effect of GA on inhibition of prostate cancer (PCa) progression by modulating the expression of HDAC1 and 2 in PCa cells. To prove our research rationale, we used diverse experimental methods. GA decreased the cell viability of only PCa cell lines and not normal cells (contrary to another HDAC inhibitor, suberoylanilide hydroxamic acid) and also inhibited colony and tumor spheroid formation. Exposure to GA decreased the mitochondrial membrane potential (ΔΨm), increased the number of apoptotic cells and induced DNA fragmentation. Western blot analysis revealed down-regulated expression of HDAC1 and 2, leading to up-regulation of acetyl-p53 expression at the protein level, subsequent to down-regulating the expression of cell-cycle-related genes, i.e., proliferating cell nuclear antigen (PCNA), Cyclin D1 and E1, up-regulating the expression of cell cycle arrest gene p21 and regulating the expression of apoptosis intrinsic pathway-related genes, such as Bax, Bcl-2, cleaved Caspase-3 and poly (ADP-ribose) polymerase 1 in both PCa cell lines. Furthermore, oral administration of GA for 8 weeks on PC-3 cells-derived tumor xenograft mice model decreases the tumor size, damages the tumor structure and down-regulates the expression of HDAC1 and 2 and PCNA in tumor mass, as confirmed by histological analysis. These results indicated that GA may hinder the PCa progression by inhibiting HDAC1 and 2 expression, thereby demonstrating the potential of GA to be used as HDACs inhibitor and anti-PCa therapeutics.
没食子酸（GA）具有多种生物活性，包括抗癌作用。组蛋白去乙酰化酶（HDACs）受肿瘤抑制基因转录调控，在多种肿瘤中过度表达，导致肿瘤的发生、发展和预后不良。本研究旨在证明 GA 通过调节 PCa 细胞中 HDAC1 和 2 的表达来抑制前列腺癌（PCa）进展的作用。为了证明我们的研究原理，我们使用了多种实验方法。GA 仅降低了 PCa 细胞系的细胞活力，而对正常细胞没有影响（与另一种 HDAC 抑制剂 suberoylanilide hydroxamic acid 不同），并且还抑制了集落和肿瘤球体的形成。暴露于 GA 会降低线粒体膜电位（ΔΨm），增加凋亡细胞的数量并诱导 DNA 片段化。Western blot 分析显示，HDAC1 和 2 的表达下调，导致乙酰化 p53 蛋白水平上调，随后下调细胞周期相关基因的表达，即增殖细胞核抗原（PCNA）、Cyclin D1 和 E1，上调细胞周期阻滞基因 p21 的表达，并调节凋亡内在途径相关基因的表达，如 Bax、Bcl-2、cleaved Caspase-3 和多聚（ADP-核糖）聚合酶 1 在两种 PCa 细胞系中。此外，GA 在 PC-3 细胞衍生的肿瘤异种移植小鼠模型中口服给药 8 周可减小肿瘤体积，破坏肿瘤结构，并下调肿瘤组织中 HDAC1 和 2 以及 PCNA 的表达，组织学分析证实了这一点。这些结果表明，GA 可能通过抑制 HDAC1 和 2 的表达来阻碍 PCa 的进展，从而证明了 GA 作为 HDACs 抑制剂和抗 PCa 治疗剂的潜力。
