Department of Genetics and Molecular Biology, Centre for Research and Advanced Studies of the National Polytechnic Institute, Mexico City 07360, Mexico.
Department of Genetics and Molecular Biology, Centre for Research and Advanced Studies of the National Polytechnic Institute, Mexico City 07360, Mexico.
Int J Oncol. 2019 May;54(5):1613-1624. doi: 10.3892/ijo.2019.4749. Epub 2019 Mar 14.
The SLC5A8 gene encodes Na monocarboxylate transporter 1, which is epigenetically inactivated in various tumour types. This has been attributed to the fact that it prevents the entry of histone deacetylase (HDAC) inhibitors and favours the metabolic reprogramming of neoplastic cells. Nevertheless, its expression and regulation in cervical cancer (CC) have not been elucidated to date. The aim of the present study was to investigate whether SLC5A8 expression is silenced in CC and if epigenetic mechanisms are involved in its regulation. Using RNA and DNA from human CC cell lines and tumour tissues from patients with CC, the expression of SLC5A8 was analysed by reverse transcription polymerase chain reaction and the methylation status of its CpG island (CGI) by bisulphite‑modified sequencing. Additionally, SLC5A8 reactivation was examined in the CC cell lines following treatment with DNA methylation (5‑aza‑2'‑deoxycytidine) and HDAC inhibitors (trichostatin A and pyruvate). All the CC cell lines and a range of tumour tissues (65.5%) exhibited complete or partial loss of SLC5A8 transcription. The bisulphite‑sequencing revealed that hypermethylation of the CGI within SLC5A8 first exon was associated with its downregulation in the majority of cases. The transporter expression was restored in the CC cell lines following exposure to 5‑aza‑2'‑deoxycytidine alone, or in combination with trichostatin A or pyruvate, suggesting that DNA methylation and histone deacetylation contribute to its inhibition in a cell line‑dependent manner. Together, the results of the present study demonstrate the key role of DNA hypermethylation in the repression of SLC5A8 in CC, as well as the involvement of histone deacetylation, at least partially. This allows for research focused on the potential function of SLC5A8 as a tumour suppressor in CC, and as a biomarker or therapeutic target in this malignancy.
SLC5A8 基因编码 Na 单羧酸转运蛋白 1，它在多种肿瘤类型中被表观遗传失活。这归因于它阻止组蛋白去乙酰化酶（HDAC）抑制剂的进入，并有利于肿瘤细胞的代谢重编程。然而，其在宫颈癌（CC）中的表达和调控尚未阐明。本研究旨在探讨 SLC5A8 的表达是否在 CC 中受到抑制，以及表观遗传机制是否参与其调控。使用来自人 CC 细胞系和 CC 患者肿瘤组织的 RNA 和 DNA，通过逆转录聚合酶链反应分析 SLC5A8 的表达，并通过亚硫酸氢盐修饰测序分析其 CpG 岛（CGI）的甲基化状态。此外，在 CC 细胞系中，用 DNA 甲基化（5-氮杂-2'-脱氧胞苷）和 HDAC 抑制剂（曲古抑菌素 A 和丙酮酸）处理后，检测 SLC5A8 的再激活情况。所有 CC 细胞系和一系列肿瘤组织（65.5%）表现出 SLC5A8 转录的完全或部分缺失。亚硫酸氢盐测序显示，SLC5A8 第一外显子中 CGI 的高度甲基化与大多数情况下的下调有关。在 CC 细胞系中，单独或与曲古抑菌素 A 或丙酮酸联合使用 5-氮杂-2'-脱氧胞苷后，转运蛋白表达得到恢复，表明 DNA 甲基化和组蛋白去乙酰化以细胞系依赖的方式共同导致其抑制。综上所述，本研究结果表明，DNA 高甲基化在 CC 中 SLC5A8 的抑制中起关键作用，组蛋白去乙酰化至少部分参与其中。这为研究 SLC5A8 作为 CC 中的肿瘤抑制因子的潜在功能以及作为该恶性肿瘤的生物标志物或治疗靶点提供了依据。
