Sodium-coupled monocarboxylate transporter is a target of epigenetic repression in cervical cancer

Hernández-Juárez,Jennifer; Vargas-Sierra,Orlando; Herrera,Luis  A.; Cantú De León,David; Fernández-Retana,Jorge; Pérez-Plasencia,Carlos; López-Camarillo,César; Gariglio,Patricio; Díaz-Chávez,José

doi:10.3892/ijo.2019.4749

Sodium-coupled monocarboxylate transporter is a target of epigenetic repression in cervical cancer

Authors:
- Jennifer Hernández-Juárez
- Orlando Vargas-Sierra
- Luis A. Herrera
- David Cantú De León
- Jorge Fernández-Retana
- Carlos Pérez-Plasencia
- César López-Camarillo
- Patricio Gariglio
- José Díaz-Chávez
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Affiliations: 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, Biomedical Unit for Cancer Research, Carcinogenesis Laboratory, Department of Basic Research, Instituto de Investigaciones Biomédicas, UNAM/Instituto Nacional de Cancerologia (INCan), Mexico City 14080, Mexico, Department of Gynaecological Oncology, National Cancer Institute, Mexico City 14080, Mexico, Biomedical Unit for Cancer Research, Carcinogenesis Laboratory, Department of Basic Research, Instituto de Investigaciones Biomédicas, UNAM/Instituto Nacional de Cancerologia (INCan), Mexico City 14080, Mexico, Laboratory of Cancer Genomics, National Cancer Institute, Mexico City 14080, Mexico, Genomic Sciences Graduate Program, Autonomous University of Mexico City, Mexico City 03100, Mexico
Published online on: March 14, 2019 https://doi.org/10.3892/ijo.2019.4749
Pages: 1613-1624
Copyright: © Hernández-Juárez et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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.

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