SETDB1 promotes the progression of colorectal cancer via epigenetically silencing p21 expression
SETDB1 promotes the progression of colorectal cancer via epigenetically silencing p21 expression
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SETDB1通过表观遗传学沉默p21表达促进结直肠癌的进展
DOI：
10.1038/s41419-020-2561-6
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发表时间：
2020-05-11
影响因子：
9
通讯作者：
Ye, Mei
中科院分区：
文献类型：
--
作者：
Cao, Nan;Yu, Yali;Ye, Mei
SETDB1 是一种组蛋白 H3K9 甲基转移酶，据报道在多种肿瘤中表达上调并促进癌症发展。然而，SETDB1 在人类结直肠癌 (CRC) 中的确切发病机制迄今尚不清楚。在这里，我们发现 SETDB1 表达在 CRC 中高度扩增。从功能上讲，SW480和HCT116细胞中SETDB1的下调减少了细胞增殖、迁移、侵袭，并增加了CRC细胞凋亡。相反，SETDB1过表达促进CRC细胞增殖、迁移和侵袭。 SETDB1 的高表达与体外更具攻击性的表型相关。流式细胞术显示SETDB1沉默后细胞周期停滞在G1期。此外，体内SETDB1的耗竭抑制了CRC细胞的增殖。从机制上讲，p21 被确定为 SETDB1 的靶标。转染siSETDB1后，p21的表达明显增加。相反，过表达SETDB1后p21的表达显着降低。我们还发现 SETDB1 可能参与 HCT116 细胞上皮间质转化（EMT）的调节。此外，我们通过双荧光素酶repoter实验证实SETDB1可以调节p21启动子的活性，并通过ChIP-PCR实验证明SETDB1可以与p21启动子结合并调节其H3K9me3富集水平。最后，我们验证了SETDB1的沉默可抑制体内结直肠癌的肿瘤发生。总之，我们的结果表明SETDB1是CRC发展的主要驱动因素，并可能为CRC的临床治疗提供新的治疗靶点。
SETDB1, a histone H3K9 methyltransferase, has been reported to be upregulated in a variety of tumors and promotes cancer development. However, the exact pathogenesis of SETDB1 in human colorectal cancer (CRC) is hitherto unknown. Here, we showed that SETDB1 expression was highly amplified in CRC. Functionally, SETDB1 downregulation in SW480 and HCT116 cells reduced cell proliferation, migration, invasion, and increased CRC cells apoptosis. In contrast, SETDB1 overexpression promoted CRC cells proliferation, migration, and invasion. High expression of SETDB1 was associated with a more aggressive phenotype in vitro. Flow cytometry showed that cell cycle was arrested in G1 phase after SETDB1 silencing. Furthermore, depletion of SETDB1 in vivo suppressed CRC cells proliferation. Mechanistically, p21 was identified as the target of SETDB1. After transfected with siSETDB1, expression of p21 was distinctly increased. In contrast, expression of p21 was significantly decreased after overexpression SETDB1. We also showed that SETDB1 could be involved in the regulation of epithelial-mesenchymal transition (EMT) in HCT116 cells. Moreover, we confirmed that SETDB1 could regulate the activity of p21 promoter by dual-luciferase repoter assay, and proved that SETDB1 could bind to the promoter of p21 and regulate its H3K9me3 enrichment level by ChIP-PCR experiment. Finally, we verified that silencing of SETDB1 inhibited CRC tumorigenesis in vivo. In conclusion, our results indicate that SETDB1 is a major driver of CRC development and might provide a new therapeutic target for the clinical treatment of CRC.