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-Rodríguez; Jesús García-Bañuelos; Claudia Frias-Gonzalez; Monica Almeida-López; Erika Martínez-López; Juan Armendariz-Borunda; Hugo Christian Monroy-Ramirez

doi:10.20944/preprints202404.0420.v1

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preprints.org > biology and life sciences > biochemistry and molecular biology > doi: 10.20944/preprints202404.0420.v1

Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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-Rodríguez

Jesús García-Bañuelos

Claudia Frias-Gonzalez

Monica Almeida-López

Erika Martínez-López

Juan Armendariz-Borunda

^* ,

Hugo Christian Monroy-Ramirez

Version 1 : Received: 4 April 2024 / Approved: 5 April 2024 / Online: 5 April 2024 (08:39:31 CEST)

How to cite: Miranda-Roblero, H.O.; Saavedra-Salazar, L.F.; Galicia-Moreno, M.; Arceo-Orozco, S.; Caloca-Camarena, F.; Sandoval-Rodríguez, A.; García-Bañuelos, J.; Frias-Gonzalez, C.; Almeida-López, M.; Martínez-López, E.; Armendariz-Borunda, J.; Monroy-Ramirez, H.C. Pirfenidone Reverts Global DNA Hypomethylation, Promoting DNMT1/UHRF/PCNA Coupling Complex in Experimental Hepatocarcinoma. Preprints 2024, 2024040420. https://doi.org/10.20944/preprints202404.0420.v1 Miranda-Roblero, H.O.; Saavedra-Salazar, L.F.; Galicia-Moreno, M.; Arceo-Orozco, S.; Caloca-Camarena, F.; Sandoval-Rodríguez, A.; García-Bañuelos, J.; Frias-Gonzalez, C.; Almeida-López, M.; Martínez-López, E.; Armendariz-Borunda, J.; Monroy-Ramirez, H.C. Pirfenidone Reverts Global DNA Hypomethylation, Promoting DNMT1/UHRF/PCNA Coupling Complex in Experimental Hepatocarcinoma. Preprints 2024, 2024040420. https://doi.org/10.20944/preprints202404.0420.v1

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MDPI and ACS Style

Miranda-Roblero, H.O.; Saavedra-Salazar, L.F.; Galicia-Moreno, M.; Arceo-Orozco, S.; Caloca-Camarena, F.; Sandoval-Rodríguez, A.; García-Bañuelos, J.; Frias-Gonzalez, C.; Almeida-López, M.; Martínez-López, E.; Armendariz-Borunda, J.; Monroy-Ramirez, H.C. Pirfenidone Reverts Global DNA Hypomethylation, Promoting DNMT1/UHRF/PCNA Coupling Complex in Experimental Hepatocarcinoma. Preprints 2024, 2024040420. https://doi.org/10.20944/preprints202404.0420.v1

APA Style

Miranda-Roblero, H.O., Saavedra-Salazar, L.F., Galicia-Moreno, M., Arceo-Orozco, S., Caloca-Camarena, F., Sandoval-Rodríguez, A., García-Bañuelos, J., Frias-Gonzalez, C., Almeida-López, M., Martínez-López, E., Armendariz-Borunda, J., & Monroy-Ramirez, H.C. (2024). Pirfenidone Reverts Global DNA Hypomethylation, Promoting DNMT1/UHRF/PCNA Coupling Complex in Experimental Hepatocarcinoma. Preprints. https://doi.org/10.20944/preprints202404.0420.v1

Chicago/Turabian Style

Miranda-Roblero, H.O., Juan Armendariz-Borunda and Hugo Christian Monroy-Ramirez. 2024 "Pirfenidone Reverts Global DNA Hypomethylation, Promoting DNMT1/UHRF/PCNA Coupling Complex in Experimental Hepatocarcinoma" Preprints. https://doi.org/10.20944/preprints202404.0420.v1

Abstract

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 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-aminofluorene (2-AAF). 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.

Keywords

Hepatocellular carcinoma; DNMT1; DNMT3a; c-Myc; β-catenin

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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