Pirfenidone Reverts Global DNA Hypomethylation, Promoting DNMT1/UHRF/PCNA Coupling Complex in Experimental Hepatocarcinoma
Hipolito Otoniel Miranda-Roblero,
Liliana Faridi Saavedra-Salazar,
Marina Galicia-Moreno,
Scarlet Arceo-Orozco,
Fernando Caloca-Camarena,
Ana Sandoval-Rodriguez,
Jesús García-Bañuelos,
Claudia Frias-Gonzalez,
Mónica Almeida-López,
Erika Martínez-López,
Juan Armendariz-Borunda,
Hugo Christian Monroy-Ramirez
Affiliations
Hipolito Otoniel Miranda-Roblero
Programa de Doctorado en Ciencias en Biología Molecular en Medicina, CUCS, University of Guadalajara, Guadalajara 44340, Mexico
Liliana Faridi Saavedra-Salazar
Programa de Doctorado en Ciencias en Biología Molecular en Medicina, CUCS, University of Guadalajara, Guadalajara 44340, Mexico
Marina Galicia-Moreno
Institute of Molecular Biology in Medicine and Gene Therapy, Department of Molecular Biology and Genomics, University Center of Health Sciences, University of Guadalajara, Guadalajara 44100, Mexico
Scarlet Arceo-Orozco
Institute of Molecular Biology in Medicine and Gene Therapy, Department of Molecular Biology and Genomics, University Center of Health Sciences, University of Guadalajara, Guadalajara 44100, Mexico
Fernando Caloca-Camarena
Institute of Molecular Biology in Medicine and Gene Therapy, Department of Molecular Biology and Genomics, University Center of Health Sciences, University of Guadalajara, Guadalajara 44100, Mexico
Ana Sandoval-Rodriguez
Institute of Molecular Biology in Medicine and Gene Therapy, Department of Molecular Biology and Genomics, University Center of Health Sciences, University of Guadalajara, Guadalajara 44100, Mexico
Jesús García-Bañuelos
Institute of Molecular Biology in Medicine and Gene Therapy, Department of Molecular Biology and Genomics, University Center of Health Sciences, University of Guadalajara, Guadalajara 44100, Mexico
Claudia Frias-Gonzalez
Programa de Doctorado en Ciencias en Biología Molecular en Medicina, CUCS, University of Guadalajara, Guadalajara 44340, Mexico
Mónica Almeida-López
University Center of Health Sciences, University of Guadalajara, Guadalajara 44340, Mexico
Erika Martínez-López
Institute of Translational Nutrigenetics and Nutrigenomics, Department of Molecular Biology and Genomics, University Center of Health Sciences, University of Guadalajara, Guadalajara 44100, Mexico
Juan Armendariz-Borunda
Institute of Molecular Biology in Medicine and Gene Therapy, Department of Molecular Biology and Genomics, University Center of Health Sciences, University of Guadalajara, Guadalajara 44100, Mexico
Hugo Christian Monroy-Ramirez
Institute of Molecular Biology in Medicine and Gene Therapy, Department of Molecular Biology and Genomics, University Center of Health Sciences, University of Guadalajara, Guadalajara 44100, Mexico
Hepatocellular carcinoma (HCC) development is associated with altered modifications in DNA methylation, changing transcriptional regulation. Emerging evidence indicates that DNA methyltransferase 1 (DNMT1) plays a key role in the carcinogenesis process. This study aimed to investigate how pirfenidone (PFD) modifies this pathway and the effect generated by the association between c-Myc expression and DNMT1 activation. Rats F344 were used for HCC development using 50 mg/kg of diethylnitrosamine (DEN) and 25 mg/kg of 2-Acetylaminofluorene (2-AAF). The HCC/PFD group received simultaneous doses of 300 mg/kg of PFD. All treatments lasted 12 weeks. On the other hand, HepG2 cells were used to evaluate the effects of PFD in restoring DNA methylation in the presence of the inhibitor 5-Aza. Histopathological, biochemical, immunohistochemical, and western blot analysis were carried out and our findings showed that PFD treatment reduced the amount and size of tumors along with decreased Glipican-3, β-catenin, and c-Myc expression in nuclear fractions. Also, this treatment improved lipid metabolism by modulating PPARγ and SREBP1 signaling. Interestingly, PFD augmented DNMT1 and DNMT3a protein expression, which restores global methylation, both in our in vivo and in vitro models. In conclusion, our results suggest that PFD could slow down HCC development by controlling DNA methylation.
