TRIM6 promotes colorectal cancer cells proliferation and response to thiostrepton by TIS21/FoxM1
TRIM6 promotes colorectal cancer cells proliferation and response to thiostrepton by TIS21/FoxM1
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TRIM6 通过 TIS21/FoxM1 促进结直肠癌细胞增殖和对硫链丝菌素的反应
DOI：
10.1186/s13046-019-1504-5
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发表时间：
2020-01-28
影响因子：
11.3
通讯作者：
Shen, Zan
中科院分区：
文献类型：
--
作者：
Zheng, Shuier;Zhou, Chenliang;Shen, Zan
背景：tripartite motif-containing proteins （TRIM）在肿瘤发生中起着重要作用。TRIM6在癌变过程中的可能功能一直受到较少关注。方法检测TRIM6在结直肠癌（CRC）组织中的表达水平。TRIM6在结直肠癌细胞系中表达下调，并进行细胞计数试剂盒-8 （CCK-8）、溴脱氧尿苷（BrdU）掺入和细胞周期测定。免疫沉淀和蛋白质组学分析鉴定TRIM6的潜在相关蛋白。结果strim6在结直肠癌中表达上调，TRIM6表达可能是结直肠癌的独立预后指标。抑制TRIM6表达抑制CRC细胞增殖，诱导细胞周期停留在G2/M期，增加对5-氟尿嘧啶和奥沙利铂的敏感性。TIS21是一种参与G2/M阻滞调控的抗增殖蛋白，被确定为TRIM6的相互作用伙伴。此外，TRIM6过表达的CRC细胞显示TIS21蛋白稳定性下降。TIS21泛素化在过表达TRIM6的CRC细胞中升高，但在过表达TRIM6 E3催化突变体（C15A）的CRC细胞中没有升高。此外，Lys5是TRIM6介导的TIS21泛素化所必需的。TIS21过表达逆转了TRIM6过表达对结直肠癌细胞增殖的诱导作用，以及叉头盒M1 （FoxM1）、磷酸化FoxM1、Cyclin B1和c-Myc的水平。Thiostrepton是FoxM1的特异性抑制剂，在体外和体内对TRIM6水平较低的CRC细胞的抗增殖活性较差。结论sour研究提示TRIM6通过TIS21/FoxM1促进结直肠癌的进展。
BackgroundTripartite motif-containing proteins (TRIM) play a crucial role in carcinogenesis. Little attention has been focused on the possible functions of TRIM6 on carcinogenesis.MethodsThe expression levels of TRIM6 were assessed in colorectal cancer (CRC) samples. TRIM6 expression was knocked down in CRC cell lines, and subjected to Cell counting kit-8 (CCK-8), bromodeoxyuridine (BrdU) incorporation and cell cycle assays. Immunoprecipitation and proteomics analysis was performed to identify potential associated proteins of TRIM6.ResultsTRIM6 expression was up-regulated in CRC samples and TRIM6 expression may be an independent prognostic marker for CRC. Knocking down TRIM6 expression suppressed CRC cell proliferation, induced cell cycle arrested at G2/M phase and increased sensitivity to 5-fluorouracil and oxaliplatin. TIS21, an anti-proliferative protein involved in the regulation of G2/M arrest, was identified as an interaction partner of TRIM6. Moreover, CRC cells with TRIM6 overexpression showed decreased TIS21 protein stability. TIS21 ubiquitination was increased in CRC cells overexpressing TRIM6, but not in those overexpressing TRIM6 E3 catalytic mutant (C15A). Further, Lys5 was essential for TRIM6 mediated TIS21 ubiquitination. TIS21 overexpression reversed the induced effects of TRIM6 overexpression on CRC cell proliferation, and the levels of forkhead box M1 (FoxM1), phosphorylated FoxM1, Cyclin B1 and c-Myc. Thiostrepton, a specific inhibitor for FoxM1, was less effective in anti-proliferative activity against CRC cells with lower level of TRIM6 in vitro and in vivo.ConclusionsOur study suggests that TRIM6 promotes the progression of CRC via TIS21/FoxM1.