Epigenetic Modulation by Phytochemicals from Nigerian Medicinal Plants in Colorectal Cancer Cells: Targeting DNMT and HDAC Pathways

Colorectal cancer (CRC) incidence is rising in Nigeria, with South West and South South urban centres recording the highest observed rates. Epigenetic dysregulation, particularly aberrant DNA methylation by DNMT enzymes and histone deacetylation by HDACs, drives oncogene silencing and tumour suppressor inactivation in CRC. Phytochemicals from Nigerian medicinal plants represent structurally diverse, potentially accessible epigenetic modifiers that remain largely unevaluated in this context. This study evaluates the epigenetic modulating activity of selected compounds from Garcinia kola (kolaviron), Morinda lucida (anthraquinones), and Cymbopogon citratus (citral) against DNMT1, DNMT3A, HDAC1, and HDAC6 in HCT116 and SW480 colorectal cancer cell lines. Enzymatic inhibition of DNMT and HDAC activity was assessed by fluorometric assays. Effects on global DNA methylation and histone acetylation were quantified by ELISA. Tumour suppressor gene re-expression (p16INK4A, RASSF1A, APC) following treatment was evaluated by RT-qPCR. Cell cycle arrest and apoptosis induction were characterised by flow cytometry. Kolaviron demonstrated dual DNMT1 and HDAC6 inhibitory activity, inducing dose-dependent demethylation of p16INK4A and re-expression of the silenced tumour suppressor. Citral selectively inhibited HDAC1 with an IC50 of 5.8 uM. Combination kolaviron plus citral treatment produced synergistic apoptosis induction. This study positions Nigerian phytochemicals as novel epigenetic CRC drug leads and proposes kolaviron as a priority candidate for pre-clinical CRC epigenetic therapy development. Keywords: colorectal cancer, epigenetics, kolaviron, DNMT, HDAC