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PARP1 regulates epigenetic processes through DNMT1 and UHRF1 in oxaliplatin-treated colon cancer cells.

Year 2025, Volume: 64 Issue: 4, 612 - 620, 08.12.2025

Venhar Gurbuz Can , Tansu Kuşat

https://doi.org/10.19161/etd.1623604

Abstract

Aim: Colon cancer is the second most commonly diagnosed cancer among females and the third most frequently diagnosed cancer among males worldwide. Epigenetics is described as alterations in gene expression without changes in nucleotide sequence. Epigenetic mechanisms can modulate the activation or inactivation of cancer-associated genes. The aim of our study was to demonstrate the epigenetic effect of PARP1, DNMT1, and UHRF1 genes in oxaliplatin-treatment colon cancer cell line.
Materials and Methods: HT-29 cells were cultured in suitable medium. Then, when the cells were grown up to a certain number, oxaliplatin was applied for 24, 48, and 72 hours at doses of 2.5, 5, 10, 25, 50, 100, and 200 µM to the HT-29 cells, and Cell viability was detected by XTT test. Following the completion of the XTT test, PARP1, DNMT1, and UHRF1 gene expression levels were analyzed by the real-time PCR method.
Results: Our results revealed that Oxaliplatin significantly suppressed the expression of UHRF1 and DNMT1 in colon cancer cells, whereas it significantly stimulated the expression of PARP1.
Conclusion: In conclusion, the data obtained indicates that the UHRF1, PARP1 and DNMT1 genes may function as modulators of the epigenome and that DNMT1 and UHRF1 interact negatively with PARP1. This study has demonstrated the potential of the UHRF1, PARP1 and DNMT1 genes as targets for colon cancer treatment and as candidate biomarkers.

Keywords

PARP1 DNMT1 UHRF1 Epigenetic Colon Cancer HT29

Project Number

yok

References

  • Liu, B. and H. Wang, Oxaliplatin induces ferroptosis and oxidative stress in HT29 colorectal cancer cells by inhibiting the Nrf2 signaling pathway. Exp Ther Med, 2022. 23(6): p. 394. DOI: 10.3892/etm.2022.11321.
  • Cheng, Y., et al., Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal Transduction and Targeted Therapy, 2019. 4(1): p. 62. DOI: 10.1038/s41392-019-0095-0.
  • Sharma, S., T.K. Kelly, and P.A. Jones, Epigenetics in cancer. Carcinogenesis, 2010. 31(1): p. 27-36. DOI: 10.1093/carcin/bgp220.
  • Lin, Y., et al., MiR-506 Targets UHRF1 to Inhibit Colorectal Cancer Proliferation and Invasion via the KISS1/PI3K/NF-κB Signaling Axis. Frontiers in Cell and Developmental Biology, 2019. 7. DOI: 10.3389/fcell.2019.00266.
  • Kong, X., et al., Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties. Cancer Cell, 2019. 35(4): p. 633-648.e7. DOI: 10.1016/j.ccell.2019.03.003.
  • Hong, Y.J., et al., Regulation of UHRF1 acetylation by TIP60 is important for colon cancer cell proliferation. Genes & Genomics, 2022. 44(11): p. 1353-1361. DOI: 10.1007/s13258-022-01298-x.
  • Kim, A. and C.A. Benavente, Oncogenic Roles of UHRF1 in Cancer. Epigenomes, 2024. 8(3): p. 26.
  • Moore, L.D., T. Le, and G. Fan, DNA Methylation and Its Basic Function. Neuropsychopharmacology, 2013. 38(1): p. 23-38. DOI: 10.1038/npp.2012.112.
  • Lakshminarasimhan, R. and G. Liang, The Role of DNA Methylation in Cancer. Adv Exp Med Biol, 2016. 945: p. 151-172. DOI: 10.1007/978-3-319-43624-1_7.
  • Dörsam, B., et al., PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression. Proc Natl Acad Sci U S A, 2018. 115(17): p. E4061-e4070. DOI: 10.1073/pnas.1712345115.
  • Taniue, K., et al., UHRF1-KAT7-mediated regulation of TUSC3 expression via histone methylation/acetylation is critical for the proliferation of colon cancer cells. Oncogene, 2020. 39(5): p. 1018-1030. DOI: 10.1038/s41388-019-1032-y.
  • Sidhu, H. and N. Capalash, UHRF1: The key regulator of epigenetics and molecular target for cancer therapeutics. Tumour Biol, 2017. 39(2): p. 1010428317692205. DOI: 10.1177/1010428317692205.
  • Mancini, M., et al., The multi-functionality of UHRF1: epigenome maintenance and preservation of genome integrity. Nucleic Acids Research, 2021. 49(11): p. 6053-6068. DOI: 10.1093/nar/gkab293.
  • Seo, J.S., et al., Hinokitiol induces DNA demethylation via DNMT1 and UHRF1 inhibition in colon cancer cells. BMC Cell Biol, 2017. 18(1): p. 14. DOI: 10.1186/s12860-017-0130-3.
  • Wang, Y., et al., UHRF1 inhibition epigenetically reprograms cancer stem cells to suppress the tumorigenic phenotype of hepatocellular carcinoma. Cell Death & Disease, 2023. 14(6): p. 381. DOI: 10.1038/s41419-023-05895-w.
  • Yamaguchi, K., et al., Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells. Nat Commun, 2024. 15(1): p. 2960. DOI: 10.1038/s41467-024-47314-4.
  • Jenkins, Y., et al., Critical role of the ubiquitin ligase activity of UHRF1, a nuclear RING finger protein, in tumor cell growth. Mol Biol Cell, 2005. 16(12): p. 5621-9. DOI: 10.1091/mbc.e05-03-0194.
  • Mousli, M., et al., ICBP90 belongs to a new family of proteins with an expression that is deregulated in cancer cells. British Journal of Cancer, 2003. 89(1): p. 120-127. DOI: 10.1038/sj.bjc.6601068.
  • Niinuma, T., et al., UHRF1 depletion and HDAC inhibition reactivate epigenetically silenced genes in colorectal cancer cells. Clinical Epigenetics, 2019. 11(1): p. 70. DOI: 10.1186/s13148-019-0668-3.
  • Foran, E., et al., Upregulation of DNA methyltransferase-mediated gene silencing, anchorage-independent growth, and migration of colon cancer cells by interleukin-6. Mol Cancer Res, 2010. 8(4): p. 471-81. DOI: 10.1158/1541-7786.Mcr-09-0496.
  • Morita, R., et al., DNA methyltransferase 1 is essential for initiation of the colon cancers. Experimental and Molecular Pathology, 2013. 94(2): p. 322-329. DOI: https://doi.org/10.1016/j.yexmp.2012.10.004.
  • Nosho, K., et al., Overexpression of poly(ADP-ribose) polymerase-1 (PARP-1) in the early stage of colorectal carcinogenesis. Eur J Cancer, 2006. 42(14): p. 2374-81. DOI: 10.1016/j.ejca.2006.01.061.
  • Wang, L., et al., PARP1in Carcinomas and PARP1Inhibitors as Antineoplastic Drugs. Int J Mol Sci, 2017. 18(10). DOI: 10.3390/ijms18102111.
  • Xu, K., et al., PARP1bound to XRCC2 promotes tumor progression in colorectal cancer. Discov Oncol, 2024. 15(1): p. 238. DOI: 10.1007/s12672-024-01112-y.
  • Ossovskaya, V., et al., Upregulation of Poly (ADP-Ribose) Polymerase-1 (PARP1) in Triple-Negative Breast Cancer and Other Primary Human Tumor Types. Genes Cancer, 2010. 1(8): p. 812-21. DOI: 10.1177/1947601910383418.
  • De Vos, M., et al., Poly(ADP-ribose) polymerase 1 (PARP1) associates with E3 ubiquitin-protein ligase UHRF1 and modulates UHRF1 biological functions. J Biol Chem, 2014. 289(23): p. 16223-38. DOI: 10.1074/jbc.M113.527424.
  • Hahm, J.Y., et al., Methylated-UHRF1 and PARP1interaction is critical for homologous recombination. BMB Rep, 2020. 53(2): p. 112-117. DOI: 10.5483/BMBRep.2020.53.2.264.
  • Zong, W., et al., PARP1: Liaison of Chromatin Remodeling and Transcription. Cancers (Basel), 2022. 14(17). DOI: 10.3390/cancers14174162.
  • Ciccarone, F., M. Zampieri, and P. Caiafa, PARP1orchestrates epigenetic events setting up chromatin domains. Seminars in Cell & Developmental Biology, 2017. 63: p. 123-134. DOI: https://doi.org/10.1016/j.semcdb.2016.11.010.
  • Li, H., et al., METTL3 promotes oxaliplatin resistance of gastric cancer CD133+ stem cells by promoting PARP1mRNA stability. Cell Mol Life Sci, 2022. 79(3): p. 135. DOI: 10.1007/s00018-022-04129-0.
  • Xu, K., et al., Combined olaparib and oxaliplatin inhibits tumor proliferation and induces G2/M arrest and γ-H2AX foci formation in colorectal cancer. Onco Targets Ther, 2015. 8: p. 3047-54. DOI: 10.2147/ott.S89154.
  • Li, H., et al., PARP1Inhibitor Combined With Oxaliplatin Efficiently Suppresses Oxaliplatin Resistance in Gastric Cancer-Derived Organoids via Homologous Recombination and the Base Excision Repair Pathway. Front Cell Dev Biol, 2021. 9: p. 719192. DOI: 10.3389/fcell.2021.719192.
  • Li, D., et al., Oxaliplatin induces the PARP1-mediated parthanatos in oral squamous cell carcinoma by increasing production of ROS. Aging (Albany NY), 2021. 13(3): p. 4242-4257. DOI: 10.18632/aging.202386.

Oxaliplatin uygulanan kolon kanseri hücrelerinde PARP1, DNMT1 ve UHRF1 üzerinden epigenetik olayları düzenler

Year 2025, Volume: 64 Issue: 4, 612 - 620, 08.12.2025

Venhar Gurbuz Can , Tansu Kuşat

https://doi.org/10.19161/etd.1623604

Abstract

Amaç: Kolon kanseri dünya genelinde kadınlarda en sık görülen ikinci, erkeklerde ise en sık görülen üçüncü kanser türüdür. Epigenetik, nükleotid diziliminde değişiklik olmaksızın gen ifadesinde meydana gelen değişiklikler olarak tanımlanmaktadır. Kanserle ilişkili genlerin aktivasyonu veya inaktivasyonu epigenetik mekanizmalarla modüle edilebilmektedir. Çalışmamızın amacı, oksaliplatin ile tedavi edilen kolon kanseri hücre hattında PARP1, DNMT1 ve UHRF1 genlerinin epigenetik etkisini gösterebilmektir.
Gereç ve Yöntem: HT-29 hücreleri uygun besiyeri ortamında kültüre edilmiş, daha sonra, belirli bir sayıya kadar büyütüldüğünde, hücrelere 2.5, 5, 10, 25, 50, 100, 200 µM dozlarında ve 24, 48 ve 72 saat boyunca oksaliplatin uygulanmıştır. Uygulama sonrasında, hücre canlılığı XTT yöntemi ile tespit edilmiştir. XTT yönteminin tamamlanmasını takiben, PARP1, DNMT1 ve UHRF1 genlerinin ekspresyon seviyeleri gerçek zamanlı PCR yöntemi ile analiz edilmiştir.
Bulgular: Oxaliplatinin kolon kanseri hücrelerinde UHRF1 ve DNMT1 ekspresyonunu önemli ölçüde baskıladığını, PARP1 ekspresyonunu ise önemli ölçüde uyardığını ortaya koymuştur.
Sonuç: Elde ettiğimiz veriler ışığında UHRF1, PARP1ve DNMT1 genlerinin epigenomun bir modülatörü olarak işlev görebileceğini ve DNMT1 ve UHRF1 genlerinin PARP1geni ile negatif korelasyon gösterdiğini tespit ettik. Bu çalışma, UHRF1, PARP1 ve DNMT1'in kolon kanseri tedavileri için potansiyel hedef ve aday biyobelirteçler olarak belirlenebileceğini göstermiştir.

Keywords

PARP1 DNMT1 UHRF1 Epigenetik Kolon kanseri HT29

Ethical Statement

Hücre hattı çalışması olduğu için Etik onay alınmamıştır

Supporting Institution

yok

Project Number

yok

Thanks

yok

References

  • Liu, B. and H. Wang, Oxaliplatin induces ferroptosis and oxidative stress in HT29 colorectal cancer cells by inhibiting the Nrf2 signaling pathway. Exp Ther Med, 2022. 23(6): p. 394. DOI: 10.3892/etm.2022.11321.
  • Cheng, Y., et al., Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal Transduction and Targeted Therapy, 2019. 4(1): p. 62. DOI: 10.1038/s41392-019-0095-0.
  • Sharma, S., T.K. Kelly, and P.A. Jones, Epigenetics in cancer. Carcinogenesis, 2010. 31(1): p. 27-36. DOI: 10.1093/carcin/bgp220.
  • Lin, Y., et al., MiR-506 Targets UHRF1 to Inhibit Colorectal Cancer Proliferation and Invasion via the KISS1/PI3K/NF-κB Signaling Axis. Frontiers in Cell and Developmental Biology, 2019. 7. DOI: 10.3389/fcell.2019.00266.
  • Kong, X., et al., Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties. Cancer Cell, 2019. 35(4): p. 633-648.e7. DOI: 10.1016/j.ccell.2019.03.003.
  • Hong, Y.J., et al., Regulation of UHRF1 acetylation by TIP60 is important for colon cancer cell proliferation. Genes & Genomics, 2022. 44(11): p. 1353-1361. DOI: 10.1007/s13258-022-01298-x.
  • Kim, A. and C.A. Benavente, Oncogenic Roles of UHRF1 in Cancer. Epigenomes, 2024. 8(3): p. 26.
  • Moore, L.D., T. Le, and G. Fan, DNA Methylation and Its Basic Function. Neuropsychopharmacology, 2013. 38(1): p. 23-38. DOI: 10.1038/npp.2012.112.
  • Lakshminarasimhan, R. and G. Liang, The Role of DNA Methylation in Cancer. Adv Exp Med Biol, 2016. 945: p. 151-172. DOI: 10.1007/978-3-319-43624-1_7.
  • Dörsam, B., et al., PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression. Proc Natl Acad Sci U S A, 2018. 115(17): p. E4061-e4070. DOI: 10.1073/pnas.1712345115.
  • Taniue, K., et al., UHRF1-KAT7-mediated regulation of TUSC3 expression via histone methylation/acetylation is critical for the proliferation of colon cancer cells. Oncogene, 2020. 39(5): p. 1018-1030. DOI: 10.1038/s41388-019-1032-y.
  • Sidhu, H. and N. Capalash, UHRF1: The key regulator of epigenetics and molecular target for cancer therapeutics. Tumour Biol, 2017. 39(2): p. 1010428317692205. DOI: 10.1177/1010428317692205.
  • Mancini, M., et al., The multi-functionality of UHRF1: epigenome maintenance and preservation of genome integrity. Nucleic Acids Research, 2021. 49(11): p. 6053-6068. DOI: 10.1093/nar/gkab293.
  • Seo, J.S., et al., Hinokitiol induces DNA demethylation via DNMT1 and UHRF1 inhibition in colon cancer cells. BMC Cell Biol, 2017. 18(1): p. 14. DOI: 10.1186/s12860-017-0130-3.
  • Wang, Y., et al., UHRF1 inhibition epigenetically reprograms cancer stem cells to suppress the tumorigenic phenotype of hepatocellular carcinoma. Cell Death & Disease, 2023. 14(6): p. 381. DOI: 10.1038/s41419-023-05895-w.
  • Yamaguchi, K., et al., Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells. Nat Commun, 2024. 15(1): p. 2960. DOI: 10.1038/s41467-024-47314-4.
  • Jenkins, Y., et al., Critical role of the ubiquitin ligase activity of UHRF1, a nuclear RING finger protein, in tumor cell growth. Mol Biol Cell, 2005. 16(12): p. 5621-9. DOI: 10.1091/mbc.e05-03-0194.
  • Mousli, M., et al., ICBP90 belongs to a new family of proteins with an expression that is deregulated in cancer cells. British Journal of Cancer, 2003. 89(1): p. 120-127. DOI: 10.1038/sj.bjc.6601068.
  • Niinuma, T., et al., UHRF1 depletion and HDAC inhibition reactivate epigenetically silenced genes in colorectal cancer cells. Clinical Epigenetics, 2019. 11(1): p. 70. DOI: 10.1186/s13148-019-0668-3.
  • Foran, E., et al., Upregulation of DNA methyltransferase-mediated gene silencing, anchorage-independent growth, and migration of colon cancer cells by interleukin-6. Mol Cancer Res, 2010. 8(4): p. 471-81. DOI: 10.1158/1541-7786.Mcr-09-0496.
  • Morita, R., et al., DNA methyltransferase 1 is essential for initiation of the colon cancers. Experimental and Molecular Pathology, 2013. 94(2): p. 322-329. DOI: https://doi.org/10.1016/j.yexmp.2012.10.004.
  • Nosho, K., et al., Overexpression of poly(ADP-ribose) polymerase-1 (PARP-1) in the early stage of colorectal carcinogenesis. Eur J Cancer, 2006. 42(14): p. 2374-81. DOI: 10.1016/j.ejca.2006.01.061.
  • Wang, L., et al., PARP1in Carcinomas and PARP1Inhibitors as Antineoplastic Drugs. Int J Mol Sci, 2017. 18(10). DOI: 10.3390/ijms18102111.
  • Xu, K., et al., PARP1bound to XRCC2 promotes tumor progression in colorectal cancer. Discov Oncol, 2024. 15(1): p. 238. DOI: 10.1007/s12672-024-01112-y.
  • Ossovskaya, V., et al., Upregulation of Poly (ADP-Ribose) Polymerase-1 (PARP1) in Triple-Negative Breast Cancer and Other Primary Human Tumor Types. Genes Cancer, 2010. 1(8): p. 812-21. DOI: 10.1177/1947601910383418.
  • De Vos, M., et al., Poly(ADP-ribose) polymerase 1 (PARP1) associates with E3 ubiquitin-protein ligase UHRF1 and modulates UHRF1 biological functions. J Biol Chem, 2014. 289(23): p. 16223-38. DOI: 10.1074/jbc.M113.527424.
  • Hahm, J.Y., et al., Methylated-UHRF1 and PARP1interaction is critical for homologous recombination. BMB Rep, 2020. 53(2): p. 112-117. DOI: 10.5483/BMBRep.2020.53.2.264.
  • Zong, W., et al., PARP1: Liaison of Chromatin Remodeling and Transcription. Cancers (Basel), 2022. 14(17). DOI: 10.3390/cancers14174162.
  • Ciccarone, F., M. Zampieri, and P. Caiafa, PARP1orchestrates epigenetic events setting up chromatin domains. Seminars in Cell & Developmental Biology, 2017. 63: p. 123-134. DOI: https://doi.org/10.1016/j.semcdb.2016.11.010.
  • Li, H., et al., METTL3 promotes oxaliplatin resistance of gastric cancer CD133+ stem cells by promoting PARP1mRNA stability. Cell Mol Life Sci, 2022. 79(3): p. 135. DOI: 10.1007/s00018-022-04129-0.
  • Xu, K., et al., Combined olaparib and oxaliplatin inhibits tumor proliferation and induces G2/M arrest and γ-H2AX foci formation in colorectal cancer. Onco Targets Ther, 2015. 8: p. 3047-54. DOI: 10.2147/ott.S89154.
  • Li, H., et al., PARP1Inhibitor Combined With Oxaliplatin Efficiently Suppresses Oxaliplatin Resistance in Gastric Cancer-Derived Organoids via Homologous Recombination and the Base Excision Repair Pathway. Front Cell Dev Biol, 2021. 9: p. 719192. DOI: 10.3389/fcell.2021.719192.
  • Li, D., et al., Oxaliplatin induces the PARP1-mediated parthanatos in oral squamous cell carcinoma by increasing production of ROS. Aging (Albany NY), 2021. 13(3): p. 4242-4257. DOI: 10.18632/aging.202386.
There are 33 citations in total.

Details

Primary Language English
Subjects Cancer Genetics, Cancer Diagnosis, Chemotherapy, Molecular Targets, Predictive and Prognostic Markers
Journal Section Research Article
Authors

Venhar Gurbuz Can 0000-0002-9777-5173

Tansu Kuşat 0000-0001-7237-1562

Project Number yok
Publication Date December 8, 2025
Submission Date January 20, 2025
Acceptance Date July 6, 2025
Published in Issue Year 2025 Volume: 64 Issue: 4

Cite

Vancouver Gurbuz Can V, Kuşat T. PARP1 regulates epigenetic processes through DNMT1 and UHRF1 in oxaliplatin-treated colon cancer cells. EJM. 2025;64(4):612-20.
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