Phytochemical Indicaxanthin Inhibits Colon Cancer Cell Growth and Affects the DNA Methylation Status by Influencing Epigenetically Modifying Enzyme Expression and Activity

Abstract

Background: Recently, we have shown anti-proliferative and pro-apoptotic effects of indicaxanthin associated with epigenetic modulation of the onco-suppressor p16^INK4a in the human colon cancer cell line CACO2. In the present study, the epigenetic activity of indicaxanthin and the mechanisms involved were further investigated in other colorectal cancer cell lines. Methods: LOVO1, CACO2, HT29, HCT116, and DLD1 cells were used to evaluate the potential influence of consistent dietary concentrations of indicaxanthin on DNA methylation, and the epigenetic mechanisms involved were researched. Results: Indicaxanthin exhibited anti-proliferative activity in all cell lines but HT29, induced demethylation in the promoters of some methylation-silenced onco-suppressor genes involved in colorectal carcinogenesis (p16^INK4a, GATA4, and ESR1), and left unchanged others which were basally hypermethylated (SFRP1 and HPP1). In apparent contrast, cell exposure to indicaxanthin increased DNMT gene expression, although indicaxanthin appeared to be an inhibitor of DNMT activity. Indicaxanthin also increased the expression of genes involved in DNA demethylation. Finally, an in silico molecular modelling approach suggested stable binding of indicaxanthin at the DNMT1 catalytic site. Conclusions: Our findings contribute to new knowledge in the field of phytochemicals and specifically suggest dietary indicaxanthin as a potential epigenetic agent to protect colon cells against tumoral alterations.

Silencing DNA methyltransferase 1 leads to the activation of the esophageal suppressor gene p16 in vitro and in vivo

“…For in vivo tumor formation, KYSE150 and KYSE410 cells (1.5x10 7 ) were isolated using trypsin-EDTA (0.05% trypsin, 0.53 mM EDTA tetrasodium salt; Gibco; Thermo Fisher Scientific, Inc.). Subsequently, 0.3 ml Protanal ® LF 10/60 sodium alginate solution (1.5%; FMC Health and Nutrition, Philadelphia, PA, USA) and 40 µl CaSO 4 (21%) were added.…”

“…DNMT1 may be as a biomarker during the course of ESCC development (4). Aberrant DNA methylation frequently occurs as a result of dysregulation of DNMTs, as has been identified in various types of human cancer, including lung, prostate, colorectal and breast cancer, which indicates that aberrant methylation substantially contributes to cancer initiation and progression (5)(6)(7)(8). Therefore, preventing the methylation of certain tumor suppressor genes may be a potential therapy for human cancer.…”

Dietary Intervention by Phytochemicals and Their Role in Modulating Coding and Non-Coding Genes in Cancer

“…Phytochemicals were demonstrated to be able to modify miRNA expression pattern and their mRNA targets, leading to the alteration of different processes involved in cancer (apoptosis cell proliferation and differentiation, angiogenesis, metastasis, and assimilation of drug resistance in cancer [6,118,120,126,127]. The let-7 family of miRNA is listed as one of the key families involved in cancer, where increased expression of this sequences can exercise a decreasing role on tumour growth [128,129,130,131,132,133].…”

Dietary phytochemical PEITC restricts tumor development via modulation of epigenetic writers and erasers

“…However, HDACs and DNMTs are also essential for the downstream maintenance of chromatin structure in the steady-state, hence non-selective inhibition of these enzymes can induce serious adverse effects that disrupt normal cell function1718. Recently, dietary phytochemicals such as indicaxanthin (Ind), genistein, and several flavones such as apigenin, chrysin, and luteolin, have been reported to decrease DNA methylation level by inhibiting DNMT activities192021. Interestingly, these flavones and Ind showed a direct interaction with DNMTs, which assessed by molecular modeling, showed possibility as good alternatives instead of chemically synthesized DNMT inhibitors2021.…”

“…Recently, dietary phytochemicals such as indicaxanthin (Ind), genistein, and several flavones such as apigenin, chrysin, and luteolin, have been reported to decrease DNA methylation level by inhibiting DNMT activities192021. Interestingly, these flavones and Ind showed a direct interaction with DNMTs, which assessed by molecular modeling, showed possibility as good alternatives instead of chemically synthesized DNMT inhibitors2021. Therefore, a more promising approach could be to identify how dietary intake of bioactive phytochemicals can promote and maintain ‘anti-tumor’ epigenetic profiles in the consumer, potentially leading to low-cost dietary interventions that protect a large fraction of the global population against cancers.…”