高级别浆液性卵巢癌(HGSOC)是卵巢癌的最致命的组织型,部分原因是其非特异性症状。ALDH1A3(醛脱氢酶1家族成员A3)是乙酰辅酶A产生的关键酶,涉及癌症的攻击行为。然而,ALDH1A3在HGSOC中的作用和分子机制仍有待阐明。使用RNA-seq和公开可用的数据集,发现ALDH1A3在HGSOC中高度表达,与不良生存有关。敲除ALDH1A3可防止HGSOC肿瘤发生并增强细胞对紫杉醇或顺铂的敏感性。发现HGSOC细胞中ALDH1A3的表达因缺氧而增加,但HIF-1α抑制剂KC7F2降低。双荧光素酶报告基因实验表明,KC7F2降低了HIF-1α过表达诱导的ALDH1A3转录活性的增加。此外,PITX1(配对像同源结构域1)被鉴定为被ALDH1A3敲低抑制,和PITX1耗尽抑制细胞增殖。机理研究表明,ALDH1A3敲除降低了组蛋白3赖氨酸27(H3K27ac)的乙酰化作用。用NaOAc处理外源乙酸盐或用Pracinostat抑制组蛋白脱乙酰酶可增加H3K27ac和PITX1水平。CHIP分析显示H3K27ac在PITX1启动子处显著富集,和ALDH1A3敲低降低了H3K27ac和PITX1之间的结合。一起来看,我们的数据表明,ALDH1A3被HIF-1α转录激活,通过增加HGSOC中PITX1启动子的H3K27ac促进肿瘤发生并降低化学敏感性。
High-grade serous ovarian cancer (HGSOC) is the most lethal histotype of ovarian cancer due to its unspecific symptoms in part.
ALDH1A3 (aldehyde dehydrogenase 1 family member A3) is a key enzyme for acetyl-CoA production involving aggressive behaviors of cancers. However,
ALDH1A3\'s effects and molecular mechanisms in HGSOC remain to be clarified. Using RNA-seq and publicly available datasets,
ALDH1A3 was found to be highly expressed in HGSOC, and associated with poor survival. Knockdown of ALDH1A3 prevented HGSOC tumorigenesis and enhanced cell sensitivity to paclitaxel or cisplatin. ALDH1A3 expression in HGSOC cells was found to be increased by hypoxia, but decreased by HIF-1α inhibitor KC7F2. The dual-luciferase reporter assay showed that the increased transcriptional activity of ALDH1A3 induced by HIF-1α overexpression was reduced by KC7F2. In addition, PITX1 (paired like homeodomain 1) was identified to be inhibited by
ALDH1A3 knockdown, and PITX1 depletion inhibited cell proliferation. The mechanistic studies showed that
ALDH1A3 knockdown reduced the acetylation of histone 3 lysine 27 (H3K27ac). Treatment of exogenous acetate with NaOAc or inhibition of histone deacetylase with Pracinostat increased H3K27ac and PITX1 levels. CHIP assay demonstrated a significant enrichment of H3K27ac at the PITX1 promoter, and ALDH1A3 knockdown reduced the binding between H3K27ac and PITX1. Taken together, our data suggest that ALDH1A3, transcriptional activated by HIF-1α, promotes tumorigenesis and decreases chemosensitivity by increasing H3K27ac of PITX1 promoter in HGSOC.