Curcumin induces re‑expression of BRCA1 and suppression of γ synuclein by modulating DNA promoter methylation in breast cancer cell lines

Abstract

Restoration of normal DNA promoter methylation and expression states of cancer-related genes may be an option for the prevention as well as the treatment of several types of cancer. Constitutional promoter methylation of BRCA1 DNA repair associated (BRCA1) gene is linked with a high risk of developing breast and ovarian cancer. Furthermore, hypomethylation of the proto-oncogene γ synuclein (SNCG) is associated with the metastasis of breast and ovarian cancer and reduced disease-free survival (DFS). In the present study, we evaluated the potential of curcumin to re-express hypermethylated BRCA1 and to suppress hypomethylated SNCG in triple-negative breast cancer (TNBC) cell line HCC-38, the estrogen receptor-negative/progesterone receptor-negative (ER-/PR-) cell line UACC-3199, and the ER + /PR + cell line T47D. The cells were treated with 5 and 10 µM curcumin for 6 days and with 5-aza-2'-deoxycytidine (5'-aza-CdR) for 48 h. Methylation-specific PCR and bisulfite pyrosequencing assays were used to assess DNA promoter methylation while gene expression levels were analyzed using quantitative real-time PCR and immunoblotting. We found that curcumin treatment restored BRCA1 gene expression by reducing the DNA promoter methylation level in HCC-38 and UACC-3199 cells and that it suppressed the expression of SNCG by inducing DNA promoter methylation in T47D cells. Notably, 5'-aza-CdR restored BRCA1 gene expression only in UACC-3199, and not in HCC-38 cells. Curcumin-induced hypomethylation of the BRCA1 promoter appears to be realized through the upregulation of the ten-eleven translocation 1 (TET1) gene, whereas curcumin-induced hypermethylation of SNCG may be realized through the upregulation of the DNA methyltransferase 3 (DNMT3) and the downregulation of TET1. Notably, miR-29b was found to be reversely expressed compared to TET1 in curcumin-and 5'-aza-CdR-treated cells, suggesting its involvement in the regulation of TET1. Overall, our results indicate that curcumin has an intrinsic dual function on DNA promoter methylation. We believe that curcumin may be considered a promising therapeutic option for treating TNBC patients in addition to preventing breast and ovarian cancer, particularly in cancer-free females harboring methylated BRCA1.

Natural Compounds That Target DNA Repair Pathways and Their Therapeutic Potential to Counteract Cancer Cells

“…The same effect on DNMT1 was reported in curcumintreated breast cancer cells, but the effects were different between cell lines. For example, in HCC-38 cells, the curcumin-dependent decrease in DNMT1 together with the inhibition of miR-29b caused an increase in TET1 (a methylcytosine dioxygenase that plays an important role in the demethylation of DNA) allowing BRCA1 re-expression, but this did not occur in T47D cells (40). It is also important to note that the response to DNA damage triggered by curcumin and varies according to the BRCA1 mutation status in triple negative breast cancer cells, but regardless of this, in all cases it leads to apoptosis (41).…”

The Impact of Natural Dietary Compounds and Food-Borne Mycotoxins on DNA Methylation and Cancer

“…Accumulating evidence indicates that the human diet is a source of micronutrients (folate, B vitamins, betaine, choline, and methionine; Figure 2 ) and bioactive compounds (curcumin, epigallocatechin-3-gallate, genistein, quercetin, resveratrol, and sulforaphane; Figure 2 ) that act as both chemopreventative and chemotherapeutic agents by modulating the epigenome [ 13 , 14 , 15 , 16 , 18 ].…”

“…Despite this, the exact mechanism by which these compounds prevent and inhibit carcinogenesis remains unclear. Emerging evidence suggests that dietary micronutrients and bioactive molecules exhibit anti-cancer properties by reversing abnormal gene activation and inhibition through epigenetic modifications such as DNA methylation [ 13 , 14 , 15 , 16 , 17 , 18 ], and these changes in DNA methylation may provide insight into future therapeutic interventions. In this review, we summarize existing literature on natural dietary micronutrients, bioactive compounds, and food-borne mycotoxins that affect DNA methylation patterns and identify its potential in the onset and treatment of cancer.…”

Epigenetic Regulation and Dietary Control of Triple Negative Breast Cancer

“…Similarly to resveratrol, curcumin was found to stimulate β-oxidation of fatty acids, inhibiting adipogenesis, and inflammation ( 90 ). Al-Yousef et al ( 91 ) recently reported that curcumin treatment restored BRCA1 expression through reduction of its promoter methylation level in TNBC cell lines HCC-38 and UACC-3199. Lower levels of BRCA1 promoter methylation were attributed to upregulation of the ten-eleven translocation 1 (TET1) gene, which mediates DNA demethylation via hydroxylation of 5-methylcytosine to 5-hydroxymethylcytosine.…”