三甲基转移酶SETD2表达下调促进结肠直肠癌细胞的迁移和增殖
Downregulation of trimethyl transferase SETD2 promotes migration and proliferation of colorectal cancer cell
Received date: 2019-05-15
Online published: 2020-04-25
目的: 研究组蛋白H3K36三甲基转移酶SETD2对结肠直肠癌(CRC)细胞发生和生长的影响。方法: 通过短发夹RNA转染降低CRC细胞系HCT116和SW480中SETD2的mRNA和蛋白质表达水平。检测转染后的CRC细胞系中三甲基化H3K36的蛋白质表达水平和肿瘤细胞增殖及迁移能力的变化,通过裸鼠成瘤实验观察KD组和对照组SETD2对于肿瘤生长的影响。结果: 在CRC细胞中,随着SETD2的mRNA及蛋白质表达水平下降,检测到三甲基化H3K36蛋白质表达下降,且CRC细胞的增殖和迁移能力显著提升(P<0.05)。在裸鼠成瘤实验中通过免疫组织化学染色法,检测到KD组的小鼠肿瘤组织内三甲基化H3K36的蛋白质表达水平明显低于对照组。KD组裸鼠肿瘤的发生时间明显早于对照组,肿瘤的直径也明显大于对照组(P<0.01)。结论: 下调SETD2的mRNA和蛋白质表达导致肿瘤组织三甲基化H3K36蛋白质表达下降,迁移和增殖能力增强,研究提示SETD2在CRC发生中的重要作用。
崔昂, 丁家增, 陈海珍, 沈晓卉, 李超飞, 刘国梁 . 三甲基转移酶SETD2表达下调促进结肠直肠癌细胞的迁移和增殖[J]. 外科理论与实践, 2020 , 25(02) : 139 -145 . DOI: 10.16139/j.1007-9610.2020.02.011
Objective: To study the effect of histone H3 lysine 36 trimethyl transferase SETD2 on colorectal cancer (CRC) cells and the tumorigenesis. Methods: The expression of SETD2 mRNA and protein decreased in CRC cell HCT116 and SW480 with transference of short hairpin RNA. There were KD group and control group. The expression of histone H3 proteins that are trimethylated on lysine 36 (H3K36me3) was detected, and the migration and proliferation capacity of two CRC cell lines were examined. The effect of SETD2 on tumor growth were observed in nude mice experiment. Results: The expression of H3K36me3 protein reduced in CRC cells following the decrease in expression of SETD2 mRNA and protein. The proliferation and migration in CRC cells increased significantly (P<0.05). H3K36me3 protein expression in tumor tissue of KD groups in nude mice experiment was much lower than that in control group by immunohistochemical staining. Tumorgenesis in KD groups occurred earlier and grew larger in size than those in control group (P<0.01). Conclusions: Downregulation of SETD2 mRNA and protein expression in CRC cells would induce the decrease of H3K36me3 protein expression in tumor tissues with migration and proliferation of tumor cells increased which suggest that SETD2 plays an important role in pathogenesis of CRC.
| [1] | Järvinen HJ, Aarnio M, Mustonen H, et al. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer[J]. Gastroenterology, 2000, 118(5):829-834. |
| [2] | Choi YJ, Oh HR, Choi MR, et al. Frameshift mutation of a histone methylation-related gene SETD1B and its regional heterogeneity in gastric and colorectal cancers with high microsatellite instability[J]. Hum Pathol, 2014, 45(8):1674-1681. |
| [3] | Faber PW, Barnes GT, Srinidhi J, et al. Huntingtin interacts with a family of WW domain proteins[J]. Hum Mol Genet, 1998, 7(9):1463-1474. |
| [4] | Yuan W, Xie J, Long C, et al. Heterogeneous nuclear ribonucleoprotein L is a subunit of human KMT3a/Set2 complex required for H3 Lys-36 trimethylation activity in vivo[J]. J Biol Chem, 2009, 284(23):15701-15707. |
| [5] | Sun XJ, Wei J, Wu XY, et al. Identification and characterization of a novel human histone H3 lysine 36-specific methyltransferase[J]. J Biol Chem, 2005, 280(42):35261-35271. |
| [6] | Wang S, Yuan X, Liu Y, et al. Genetic polymorphisms of histone methyltransferase SETD2 predicts prognosis and chemotherapy response in Chinese acute myeloid leukemia patients[J]. J Transl Med, 2019, 17(1):101. |
| [7] | Kim IK, McCutcheon JN, Rao G, et al. Acquired SETD2 mutation and impaired CREB1 activation confer cisplatin resistance in metastatic non-small cell lung cancer[J]. Oncogene, 2019, 38(2):180-193. |
| [8] | Chen Z, Raghoonundun C, Chen W, et al. SETD2 indicates favourable prognosis in gastric cancer and suppresses cancer cell proliferation, migration, and invasion[J]. Biochem Biophys Res Commun, 2018, 498(3):579-585. |
| [9] | Lowe BR, Maxham LA, Hamey JJ, et al. Histone H3 mutations: an updated view of their role in chromatin dere-gulation and cancer[J]. Cancers (Basel), 2019, 11(5):pii: E660. |
| [10] | Walter DM, Venancio OS, Buza EL, et al. Systematic in vivo inactivation of chromatin-regulating enzymes identifies Setd2 as a potent tumor suppressor in lung adenocarcinoma[J]. Cancer Res, 2017, 77(7):1719-1729. |
| [11] | Carrozza MJ, Li B, Florens L, et al. Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription[J]. Cell, 2005, 123(4):581-592. |
| [12] | Carvalho S, Raposo AC, Martins FB, et al. Histone methyltransferase SETD2 coordinates FACT recruitment with nucleosome dynamics during transcription[J]. Nucleic Acids Res, 2013, 41(5):2881-2893. |
| [13] | Li F, Mao G, Tong D, et al. The histone mark H3K36me3 regulates human DNA mismatch repair through its inte-raction with MutSa[J]. Cell, 2013, 153(3):590-600. |
| [14] | Li L, Miao W, Huang M, et al. Integrated genomic and proteomic analyses reveal novel mechanisms of the methyltransferase SETD2 in renal cell carcinoma deve-lopment[J]. Mol Cell Proteomics, 2019, 18(3):437-447. |
| [15] | Carvalho S, Vítor AC, Sridhara SC, et al. SETD2 is required for DNA double-strand break repair and activation of the p53-mediated checkpoint[J]. Elife, 2014, 3:e02482. |
| [16] | Yuan H, Li N, Fu D, et al. Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis[J]. J Clin Invest, 2017, 127(9):3375-3391. |
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