组蛋白去乙酰化酶(Histone deacetylases, HDACs)催化组蛋白去乙酰化,与细胞增殖、分化及凋亡等诸多过程密切相关。HDAC抑制剂(HADC inhibitors, HADCIs)具有潜在的抗肿瘤作用,是近年药物筛查的热点之一。近期研究提示HDAC2可通过影响细胞代谢过程发挥抗肿瘤作用,但各类HDACIs调控代谢过程的机制尚待研究。本研究以肝细胞系(HepG2)为研究对象,整合比较了两种HDACIs(TSA和SAHA)的表达谱数据。在TSA处理组中,筛查到380个差异表达基因(DEGs)及35个DEGs富集的KEGG通路;SAHA处理组的表达分析印证了大多数DEGs(177/380)和富集通路(23/35)。比较分析发现,在这两类HDACIs共同影响的通路中,近一半通路(9/23)与代谢有关;近1/3共享DEGs(66/177)参与代谢过程。通过HDAC2 siRNA细胞实验证实了TSA和SAHA对代谢基因的影响。本研究结果显示HDACIs在治疗肿瘤等代谢性疾病方面具有潜在的应用 价值。
Histone deacetylases (HDACs) are responsible for catalyzing the deacetylation of histones, which closely related to many biological processes such as cell proliferation, differentiation and apoptosis. In recent years, HDAC inhibitors (HADCIs), with the anti-tumor potential, have been hot-spots of drug screening. Although the latest studies suggested that HDAC2 might influence the metabolism, the mechanism of HDACIs in metabolic regulation is still unclear. Here, we integrated the gene expression profiling of HDACIs (TSA and SAHA) in hepatocellular carcinoma cell (HepG2). The results showed 380 differentially expressed genes (DEGs) and 35 KEGG pathways enriched by DEGs in TSA-treatment group. Most of DEGs (177/380) and KEGG pathways (23/35) from TSA-treatment groups were confirmed by SAHA-treatment. About half of KEGG pathways (9/23) were related to metabolism ,and nearly one third of common DEGs (66/177) were involved in metabolic process. Moreover, HDAC2 siRNA experiment verified the effect of HDACIs on metabolic genes, suggesting that HDACIs potentially present a practical value to prevent tumor and other metabolism-related diseases.
[1] 张振沛, 李德海, 顾谦群, 栾业鹏. 选择性HDAC抑制剂的研究进展. 中国药物化学杂志, 2013, 23(4): 321-330.
[2] Deng CC, Lipstein M, Rodriguez R, Jirau Serrano XO, McIntosh C, Tsai WY, Wasmuth AS, Jaken S, O'Connor OA. The novel IKK2 inhibitor LY2409881 potently synergizes with histone deacetylase inhibitors in preclinical models of lymphoma through the downregulation of NF-κB. Clin Cancer Res , 2015, 21(1): 134-145.
[3] Lübbert M, Kuendgen A. Combining DNA methyltransferase and histone deacetylase inhibition to treat acute myeloid leukemia/myelodysplastic syndrome: Achievements and challenges. Cancer , 2015, 121(4): 498-501.
[4] Chen XM, Xie XB, Zhao Q, Wang F, Bai Y, Yin JQ, Jiang H, Xie XL, Jia Q, Huang G. Ampelopsin induces apoptosis by regulating multiple c-Myc/S-phase kinase-associated protein 2/F-box and WD repeat-containing protein 7/histone deacetylase 2 pathways in human lung adenocarcinoma cells. Mol Med Rep , 2015, 11(1): 105-112.
[5] Shen Q, Tang WF, Sun J, Feng LF, Jin HC, Wang X. Regulation of CRADD-caspase 2 cascade by histone deacetylase 1 in gastric cancer. Am J Transl Res , 2014, 6(5): 538-547.
[6] Zhu XJ, Liu J, Xu XY, Zhang CD, Dai DQ. The Pleckstrin and Sec7 domain-containing gene as a novel epigenetic modification marker in human gastric cancer and its clinical significance. Int J Oncol , 2015, 46(1): 195-204.
[7] Li YL, Yang TS, Ruan WM, Cui W, Jin Y, Zou XM. Effect of trichostatin a on SGC-7901 gastric cancer cells. Int J Clin Exp Med , 2014, 7(8): 1958-1966.
[8] Shi QQ, Zuo GW, Feng ZQ, Zhao LC, Luo L, You ZM, Li DY, Xia J, Li J, Chen DL. Effect of trichostatin A on anti HepG2 liver carcinoma cells: inhibition of HDAC activity and activation of Wnt/β-Catenin signaling. Asian Pac J Cancer Prev , 2014, 15(18): 7849-7855.
[9] Yang XL, Zhang CD, Wu HY, Wu YH, Zhang YN, Qin MB, Wu H, Liu XC, Lina X, Lu SM. Effect of trichostatin A on CNE2 nasopharyngeal carcinoma cells-genome-wide DNA methylation alteration. Asian Pac J Cancer Prev , 2014, 15(11): 4663-4670.
[10] Yang DH, Lee JW, Lee J, Moon EY. Dynamic rearrangement of F-actin is required to maintain the antitumor effect of trichostatin A. PLoS One , 2014, 9(5): e97352.
[11] Peiffer L, Poll-Wolbeck SJ, Flamme H, Gehrke I, Hallek M, Kreuzer KA. Trichostatin A effectively induces apoptosis in chronic lymphocytic leukemia cells via inhibition of Wnt signaling and histone deacetylation. J Cancer Res Clin Oncol , 2014, 140(8): 1283-1293.
[12] Xiong JJ, Xu XY, Zhou XO, Liu JY, Gong Z, Wu P, Li WD. USP22 transcriptional activity is negatively regulated by the histone deacetylase inhibitor trichostatin A. Mol Med Rep , 2014, 10(6): 3343-3347.
[13] Lee YH, Seo D, Choi KJ, Andersen JB, Won MA, Kitade M, Gómez-Quiroz LE, Judge AD, Marquardt JU, Raggi C, Conner EA, MacLachlan I, Factor VM, Thorgeirsson SS. Antitumor effects in hepatocarcinoma of isoform-selective inhibition of HDAC2. Cancer Res , 2014, 74(17): 4752-4761.
[14] Chittur SV, Sangster-Guity N, McCormick PJ. Histone deacetylase inhibitors: a new mode for inhibition of cholesterol metabolism. BMC Genomics , 2008, 9: 507.
[15] Nunes MJ, Moutinho M, Gama MJ, Rodrigues CMP, Rodrigues E. Histone deacetylase inhibition decreases cholesterol levels in neuronal cells by modulating key genes in cholesterol synthesis, uptake and efflux. PLoS One , 2013, 8(1): e53394.
[16] Nunes MJ, Moutinho M, Milagre I, Gama MJ, Rodrigues E. Okadaic acid inhibits the trichostatin A-mediated increase of human CYP46A1 neuronal expression in a ERK1/2-Sp3-dependent pathway. J Lipid Res , 2012, 53(9): 1910-1919.
[17] Milagre I, Nunes MJ, Moutinho M, Rivera I, Fuso A, Scarpa S, Gama MJ, Rodrigues E. Chromatin-modifying agents increase transcription of CYP46A1, a key player in brain cholesterol elimination. J Alzheimers Dis , 2010, 22(4): 1209-1221.
[18] Chittur SV, Sangster-Guity N, McCormick PJ. Histone deacetylase inhibitors: a new mode for inhibition of c
