RESUMO
Objective @#To investigate the effects of DNA demethylation drugs combined with histone deacetylase inhibitors on fragile X mental retardation 1 neighbor protein (FMR1NB) expression and its promoter methylation in human oral cancer cells and try to find a strategy of weakening the heterogeneity of FMR1NB expression .@*Methods@#Human oral cancer cell lines C al27 and SCC⁃9 were treated with decitabine (DAC) , an inhibitor of DNA methyltransferase , combined with trichostatin A ( TSA) and valproic acid ( VPA) , inhibitors of histone deacetylase . Then reverse transcription⁃polymerase chain reaction ( RT⁃PCR) , quantitative real ⁃time PCR ( qRT⁃PCR) and Western blot were used to detect the expression of FMR1NB and pyrosequencing was used to detect the methylation of FMR1NB promoter. @*Results @#Compared with the blank control group , DAC and its combination with TSA and VPA significantly induced the expression of FMR1NB mRNA and protein in C al27 and SCC⁃9 cells . Compared with DAC alone group , FMR1NB mRNA expression of each DAC⁃combined drug groups significantly increased , but FMR1NB protein did not significantly change in C al27 cells; for SCC⁃9 cells , except for DAC + TSA group , the mRNA and protein levels of FMR1NB significantly increased in all other groups . In addition , there was no significant difference in the expression of FMR1NB mRNA and protein between the three⁃combined drugs group and two-combined drugs groups . Further methylation assay showed that the methylation level of the overall FMR1NB promoter and its each CpG site measured were reduced to varying degrees in all treatment groups except for three⁃combination drug group of SCC⁃9 .@*Conclusion @#DAC and its combination with TSA and VPA can enhance the expression of FMR1NB by mediating the demethylation of FMR1NB promoter , wherein the enhanced expression effect of the combination of the two drugs is stronger , suggesting that they have the potential to weaken the heterogeneity of FMR1NB expression and improve the immunotherapy effect of oral cancer.
RESUMO
Resumen Los cambios epigenéticos juegan en el organismo un papel importante en el control de la expresión génica, durante el desarrollo y a lo largo de toda la vida, sobre todo durante el envejecimiento. En los últimos años se han acumulado evidencias que avalan la participación de los procesos epigenéticos en el desarrollo y evolución de diversas enfermedades como procesos tumorales, enfermedades genéticas, cardiovasculares y neurodegenerativas. Además, los marcadores epigenéticos (metilación del ADN, modificaciones en las histonas y los ARN no codificantes) podrían indicar la predisposición del individuo a determinados procesos patológicos. La administración de fármacos epigenéticos ha demostrado ser eficiente en el tratamiento de enfermedades tales como la aterosclerosis, neoplasias, procesos neurodegenerativos, enfermedades hepáticas, etc. En este artículo se abordarán algunos ejemplos de la contribución que las modificaciones epigenéticas dan a la patogenia de las enfermedades neurodegenerativas y cardiovasculares. En el futuro, la bioquímica clínica será frecuentemente utilizada en los análisis epigenéticos y ayudará al diseño de fármacos y estrategias terapéuticas dirigidas a modificar el epigenoma.
Abstract In the organism, epigenetic changes play an important role in the control of gene expression, during its development and throughout life, especially during ageing. In recent years, evidence has accumulated that supports the participation of epigenetic processes in the development and evolution of various diseases such as tumor processes, genetic, cardiovascular and neurodegenerative diseases. In addition, epigenetic markers (DNA methylation, histone modifications and non-coding RNAs) could indicate the predisposition to certain pathological processes. The administration of epigenetic drugs has proven to be efficient in the treatment of diseases such as atherosclerosis, neoplasms, neurodegenerative processes, liver diseases, etc. In this article we will address some examples of the contribution that epigenetic modifications give to the pathogenesis of neurodegenerative and cardiovascular diseases. In the future, clinical biochemistry will be frequently used in epigenetic analyzes and will help design drugs and therapeutic strategies aimed to modify the epigenome.
Resumo As alterações epigenéticas têm no organismo um papel importante no controle da expressão gênica durante o desenvolvimento e ao longo de toda a vida, principalmente durante o envelhecimento. Nos últimos anos, foram acumuladas evidências que demonstram a participação dos processos epigenéticos no desenvolvimento e evolução de diversas doenças como, por exemplo, processos tumorais, doenças genéticas, cardiovasculares e neurodegenerativas. Além disso, os marcadores epigenéticos (metilação do DNA, modificações nas histonas e nos RNA não codificantes), poderiam indicar a predisposição do indivíduo a determinados processos patologicos. A administração de fármacos epigenéticos demonstrou ser eficiente no tratamento de doenças tais como a aterosclerose, neoplasias, processos neurodegenerativos, doenças hepáticas, etc. Neste estudo abordaremos alguns exemplos da contribuição que as alterações epigenéticas dão à patogenia das doenças neurodegenerativas e cardiovasculares. No futuro, a bioquímica clínica será frequentemente utilizada nas análises epigenéticas e ajudará ao desenho de medicamentos e estratégias terapêuticas dirigidas a modificar o epigenoma.