Naik Debasmita, Kalle Arunasree M
Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana State, 500046, India.
Noncoding RNA Res. 2024 Feb 27;9(3):732-743. doi: 10.1016/j.ncrna.2024.02.009. eCollection 2024 Sep.
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.
宫颈癌是全球女性死亡的主要原因之一，表现出多种影响基因表达和信号通路的分子异常。表观遗传因素，包括组蛋白去乙酰化酶（HDACs）如HDAC8和HDAC6，以及微小RNA（miRNAs），在宫颈癌进展中起关键作用。最近的研究揭示了miRNAs作为HDACs的潜在调节因子，提供了一条有前景的治疗途径。本研究采用计算机miRNA预测、qRT-PCR共表达研究和双荧光素酶报告基因检测，以鉴定在宫颈癌HeLa细胞中调控HDAC8和HDAC6的miRNAs。结果确定miR-497-3p和miR-324-3p分别为HDAC8和HDAC6的新型负调节因子。功能分析表明，HeLa细胞中miR-497-3p的过表达抑制了HDAC8，导致下游靶点p53和α-微管蛋白的乙酰化增加。同样，miR-324-3p的过表达抑制了HDAC6的mRNA和蛋白表达，增强了Hsp90和α-微管蛋白的乙酰化。值得注意的是，通过miRNA过表达抑制HDAC8与HeLa细胞活力降低、上皮-间质转化（EMT）减少以及微管束形成增加相关。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miRNAs在宫颈癌细胞中的高表达有望抑制转移，为宫颈癌的干预提供了一种靶向方法。
