Zhang Shi-Lan, Du Xiao, Tan Lin-Na, Deng Fei-Hong, Zhou Bing-Yi, Zhou He-Jun, Zhu Hong-Yi, Chu Yi, Liu De-Liang, Tan Yu-Yong
Department of Gastroenterology, The Second Xiangya Hospital, Central South University Changsha 410011, Hunan, P.R. China.
Am J Transl Res. 2020 Feb 15;12(2):602-611. eCollection 2020.
SET7 is the first lysine methyltransferase and plays vital roles in tumorigenesis. This study aims to seek clinical value of SET7 in colorectal cancer (CRC) patients, along with its biological impact on cell proliferation and migration. In patients with CRC, the expression of SET7 in cancer tissue was significantly lower than that in adjacent tissue, and down-regulated SET7 was closely correlated with poor prognosis. Loss-of-function and gain-of-function studies indicated that SET7 inhibited cell proliferation and migration by acting on HDAC6 substrate in colon cancer cells. Besides, the co-immunoprecipitation assay showed that SET7 and HDAC6 can interact reciprocally. The interaction effect between SET7 and HDAC6 could significantly reduce cell viability, scratch healing rate, and migrated cells in colon cancer cells. Instead of acting on each endogenous expression, the results demonstrated that the level of acetylated α-tubulin was greatly decreased in HDAC6 overexpression group, while significantly increased in SET7 overexpressed group. However, changes were partly restored in both SET7 and HDAC6-transfected group. On the contrary, the expression of acetylated α-tubulin protein was significantly increased in HDAC6 knockdown group, but higher in both HDAC6 and SET7 silencing group. These results indicated that SET7 played a role in tumor suppression via increasing levels of acetylated-α-tubulin mediated by HDAC6. In addition, the interaction effect significantly decreased the ratios of p-ERK/ERK, which indicated that it may partly suppress ERK signaling pathway. In conclusion, SET7 is a promising therapeutic target for preventing metastasis and improving prognosis in colon cancer.
SET7是首个赖氨酸甲基转移酶，在肿瘤发生过程中发挥着至关重要的作用。本研究旨在探寻SET7在结直肠癌（CRC）患者中的临床价值，以及其对细胞增殖和迁移的生物学影响。在CRC患者中，癌组织中SET7的表达显著低于癌旁组织，且SET7表达下调与预后不良密切相关。功能缺失和功能获得研究表明，SET7通过作用于结肠癌细胞中的HDAC6底物来抑制细胞增殖和迁移。此外，免疫共沉淀试验表明SET7和HDAC6可相互作用。SET7与HDAC6之间的相互作用效应可显著降低结肠癌细胞的细胞活力、划痕愈合率和迁移细胞数量。结果表明，与作用于各自内源性表达不同，HDAC6过表达组中乙酰化α-微管蛋白水平大幅降低，而SET7过表达组中该水平显著升高。然而，在SET7和HDAC6转染组中，这种变化部分得到恢复。相反，HDAC6敲低组中乙酰化α-微管蛋白的表达显著增加，但在HDAC6和SET7沉默组中更高。这些结果表明，SET7通过增加由HDAC6介导的乙酰化-α-微管蛋白水平发挥肿瘤抑制作用。此外，相互作用效应显著降低了p-ERK/ERK的比率，这表明它可能部分抑制ERK信号通路。总之，SET7是预防结肠癌转移和改善预后的一个有前景的治疗靶点。
