组蛋白甲基转移酶 SETD1A 与 notch 相互作用，并促进 notch 转录激活，从而增强卵巢癌的发展。
Histone methyltransferase SETD1A interacts with notch and promotes notch transactivation to augment ovarian cancer development.
机构信息
Department of Gynecology and Obstetrics, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
出版信息
BMC Cancer. 2023 Jan 27;23(1):96. doi: 10.1186/s12885-023-10573-3.
BACKGROUND
High expression of SETD1A, a histone methyltransferase that specifically methylates H3K4, acted as a key oncogene in several human cancers. However, the function and underlying molecular mechanism of SETD1A in ovarian cancer (OV) remain markedly unknown.
METHODS
The expression of SETD1A in OV were detected by Western blot and analyzed online, and the prognosis of STED1A in OV were analyzed online. The protein and mRNA levels were determined by Western blot and RT-qPCR. The cell proliferatin, migration and invasion were measured by CCK-8 and transwell assays. The protein interaction was detected by co-IP assay. The interaction between protein and DNA was performed by ChIP assay. The tumor growth in vivo was performed by xenograft tumor model.
RESULTS
SETD1A was overexpressed in OV and a predictor of poor prognosis. Overexpression of SETD1A augmented the abilities of cell proliferation, migration, and invasion in MRG1 and OVCAR5 cells. In comparison, SETD1A knockdown suppressed cell growth, migration, and invasion in SKOV3 and Caov3 cells. Specifically, SETD1A enhanced Notch signaling by promoting the expression of Notch target genes, such as Hes1, Hey1, Hey2, and Heyl. Mechanistically, SETD1A interacted with Notch1 and methylated H3K4me3 at Notch1 targets to enhance Notch signaling. In addition, restoration of Notch1 in SETD1A-knockdown OV cells recovered cell proliferation, migration and invasion, which was inhibited by SETD1A knockdown. Furthermore, reduction of SETD1A suppressed tumorigenesis in vivo.
CONCLUSION
In conclusion, our results highlighted the key role of SETD1A in OV development and proved that SETD1A promotes OV development by enhancing Notch1 signaling, indicating that SETD1A may be a novel target for OV treatment.
背景
组蛋白甲基转移酶 SETD1A 特异性地甲基化 H3K4，其高表达可作为几种人类癌症的关键癌基因。然而，SETD1A 在卵巢癌（OV）中的功能和潜在的分子机制仍显著未知。
方法
通过 Western blot 和在线分析检测 OV 中 SETD1A 的表达，并在线分析 SETD1A 在 OV 中的预后。通过 Western blot 和 RT-qPCR 测定蛋白和 mRNA 水平。通过 CCK-8 和 Transwell 测定细胞增殖、迁移和侵袭。通过 co-IP 测定检测蛋白相互作用。通过 ChIP 测定检测蛋白与 DNA 的相互作用。通过异种移植肿瘤模型进行体内肿瘤生长实验。
结果
SETD1A 在 OV 中过表达，是预后不良的预测因子。SETD1A 的过表达增强了 MRG1 和 OVCAR5 细胞中细胞增殖、迁移和侵袭的能力。相比之下，SETD1A 的敲低抑制了 SKOV3 和 Caov3 细胞的生长、迁移和侵袭。具体而言，SETD1A 通过促进 Notch 靶基因如 Hes1、Hey1、Hey2 和 Heyl 的表达增强了 Notch 信号。在机制上，SETD1A 与 Notch1 相互作用，并在 Notch1 靶标上甲基化 H3K4me3 以增强 Notch 信号。此外，在 SETD1A 敲低的 OV 细胞中恢复 Notch1 恢复了细胞增殖、迁移和侵袭，而 SETD1A 敲低则抑制了这些作用。此外，降低 SETD1A 抑制了体内肿瘤发生。
结论
总之，我们的研究结果强调了 SETD1A 在 OV 发展中的关键作用，并证明 SETD1A 通过增强 Notch1 信号促进 OV 发展，表明 SETD1A 可能成为 OV 治疗的新靶点。
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