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Article

Epigenetic Remodeling of Regulatory Regions by Indicaxanthin Suggests a Shift in Cell Identity Programs in Colorectal Cancer Cells

by
Maria Antonietta Ragusa
1,
Carla Gentile
1,
Aldo Nicosia
2,
Salvatore Costa
1,
Sara Volpes
1,
Laura Greco
1,3,
Flores Naselli
1,* and
Fabio Caradonna
1,4
1
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Sezione di Biologia Cellulare, Università di Palermo, Viale delle Scienze, Ed. 16, 90128 Palermo, Italy
2
Institute for Biomedical Research and Innovation-National Research Council (IRIB-CNR), 90146 Palermo, Italy
3
Dipartimento di Scienze della Terra e del Mare, Università di Palermo, 90123 Palermo, Italy
4
National Biodiversity Future Center (NBFC), 90133 Palermo, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(13), 6072; https://doi.org/10.3390/ijms26136072
Submission received: 30 May 2025 / Revised: 20 June 2025 / Accepted: 23 June 2025 / Published: 24 June 2025
(This article belongs to the Special Issue Fundamental and Translational Insights into Colorectal Cancer)
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Abstract

Aberrant DNA methylation is a hallmark of colorectal cancer (CRC), contributing to tumor progression through the silencing of tumor suppressor genes and activation of oncogenes. Indicaxanthin (IND), a dietary betalain pigment from Opuntia ficus indica, has shown antiproliferative effects in CRC models, yet its epigenetic impact remains unexplored. In this study, we investigated the effects of IND on the methylome of Caco-2 cells using Reduced Representation Bisulfite Sequencing (RRBS). IND induced a global hypermethylation profile, particularly at gene promoters and CpG islands. Among the differentially methylated genes, 60% were protein-coding, and 10% encoded transcription factors, including PAX5 and TFAP4, both hypermethylated at active enhancers. Functional enrichment analysis revealed pathways beyond canonical intestinal functions, suggesting altered cell identity and plasticity. Transcription factor targets (SOX10, NFKB1, AHR, ARNT) were significantly enriched among the affected genes, several of which are involved in transdifferentiation processes. Methylation changes also indicated potential reprogramming toward epithelial cell types from pulmonary or neuroectodermal origin. Moreover, IND induced selective hypomethylation of Alu elements on chromosome 21 and hypermethylation of rDNA loci, hinting at suppressed ribosomal biogenesis. Overall, these findings highlight the epigenetic remodeling potential of IND and its possible role in modulating cell fate and metabolism in CRC cells.
Keywords: Indicaxanthin; phytochemical; Methylomic signature; colorectal cancer Indicaxanthin; phytochemical; Methylomic signature; colorectal cancer

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MDPI and ACS Style

Ragusa, M.A.; Gentile, C.; Nicosia, A.; Costa, S.; Volpes, S.; Greco, L.; Naselli, F.; Caradonna, F. Epigenetic Remodeling of Regulatory Regions by Indicaxanthin Suggests a Shift in Cell Identity Programs in Colorectal Cancer Cells. Int. J. Mol. Sci. 2025, 26, 6072. https://doi.org/10.3390/ijms26136072

AMA Style

Ragusa MA, Gentile C, Nicosia A, Costa S, Volpes S, Greco L, Naselli F, Caradonna F. Epigenetic Remodeling of Regulatory Regions by Indicaxanthin Suggests a Shift in Cell Identity Programs in Colorectal Cancer Cells. International Journal of Molecular Sciences. 2025; 26(13):6072. https://doi.org/10.3390/ijms26136072

Chicago/Turabian Style

Ragusa, Maria Antonietta, Carla Gentile, Aldo Nicosia, Salvatore Costa, Sara Volpes, Laura Greco, Flores Naselli, and Fabio Caradonna. 2025. "Epigenetic Remodeling of Regulatory Regions by Indicaxanthin Suggests a Shift in Cell Identity Programs in Colorectal Cancer Cells" International Journal of Molecular Sciences 26, no. 13: 6072. https://doi.org/10.3390/ijms26136072

APA Style

Ragusa, M. A., Gentile, C., Nicosia, A., Costa, S., Volpes, S., Greco, L., Naselli, F., & Caradonna, F. (2025). Epigenetic Remodeling of Regulatory Regions by Indicaxanthin Suggests a Shift in Cell Identity Programs in Colorectal Cancer Cells. International Journal of Molecular Sciences, 26(13), 6072. https://doi.org/10.3390/ijms26136072

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