PDF(Pubmed)
Abstract：
Cervical cancer, a leading global cause of female mortality, exhibits diverse molecular aberrations influencing gene expression and signaling pathways. Epigenetic factors, including histone deacetylases (HDACs) such as HDAC8 and HDAC6, along with microRNAs (miRNAs), play pivotal roles in cervical cancer progression. Recent investigations have unveiled miRNAs as potential regulators of HDACs, offering a promising therapeutic avenue. This study employed in-silico miRNA prediction, qRT-PCR co-expression studies, and Dual-Luciferase reporter assays to identify miRNAs governing HDAC8 and HDAC6 in HeLa, cervical cancer cells. Results pinpointed miR-497-3p and miR-324-3p as novel negative regulators of HDAC8 and HDAC6, respectively. Functional assays demonstrated that miR-497-3p overexpression in HeLa cells suppressed HDAC8, leading to increased acetylation of downstream targets p53 and α-tubulin. Similarly, miR-324-3p overexpression inhibited HDAC6 mRNA and protein expression, enhancing acetylation of Hsp90 and α-tubulin. Notably, inhibiting HDAC8 via miRNA overexpression correlated with reduced cell viability, diminished epithelial-to-mesenchymal transition (EMT), and increased microtubule bundle formation in HeLa cells. In conclusion, miR-497-3p and miR-324-3p emerge as novel negative regulators of HDAC8 and HDAC6, respectively, with potential therapeutic implications. Elevated expression of these miRNAs in cervical cancer cells holds promise for inhibiting metastasis, offering a targeted approach for intervention in cervical malignancy.
摘要：
宫颈癌,全球女性死亡的主要原因，表现出不同的分子畸变影响基因表达和信号通路。表观遗传因素,包括组蛋白脱乙酰酶（HDACs），如HDAC8和HDAC6，以及microRNAs（miRNAs），在宫颈癌进展中起关键作用。最近的研究揭示了miRNA作为HDAC的潜在调节因子，提供了一个有希望的治疗途径。本研究采用计算机内miRNA预测，qRT-PCR共表达研究，和双荧光素酶报告基因分析，以鉴定HeLa中控制HDAC8和HDAC6的miRNA，宫颈癌细胞。结果确定miR-497-3p和miR-324-3p分别是HDAC8和HDAC6的新型负调节因子。功能测定表明，miR-497-3p在HeLa细胞中的过表达抑制HDAC8，导致下游靶标p53和α-微管蛋白的乙酰化增加。同样，miR-324-3p过表达抑制HDAC6mRNA和蛋白表达,增强Hsp90和α-微管蛋白的乙酰化。值得注意的是,通过与细胞活力降低相关的miRNA过表达抑制HDAC8，上皮-间质转化（EMT）减少，并增加了HeLa细胞中微管束的形成。总之,miR-497-3p和miR-324-3p分别成为HDAC8和HDAC6的新型负调节因子。具有潜在的治疗意义。这些miRNA在宫颈癌细胞中的表达升高有望抑制转移，为宫颈恶性肿瘤的干预提供了有针对性的方法。
