Curcumin‑induced promoter hypermethylation of the mammalian target of rapamycin gene in multiple myeloma cells

Abstract

Curcumin, a polyphenol derived from the rhizome of Curcuma, is a potential tumor inhibitor through affecting signaling pathways and epigenetic regulation. The mammalian target of rapamycin (mTOR) gene serves a crucial role in the carcinogenesis of multiple myeloma. The curcumin-induced epigenetic regulation of mTOR, including promoter DNA methylation in multiple myeloma, has not yet been fully elucidated. In the present study, antitumor effects of curcumin were investigated in RPMI-8226 and NCI-H929 cells using an MTT assay and flow cytometry. The expression of mTOR and DNA methyltransferase proteins were determined by western blot analysis, and the methylation status of the mTOR promoter were detected by sequencing following bisulfite conversion. The results of the present study revealed that the half-maximal inhibitory concentration of curcumin was 10 µM in myeloma cells. Following curcumin treatment, the mRNA and protein expression levels of mTOR were decreased by 43.31 and 39.34% in NCI-H929 cells, respectively. The promoter of mTOR, located in chromosome 1 (chromosome position, 11262153-11263153), contains a CpG island that was hypermethylated in myeloma cells following curcumin treatment. The expression levels of DNA methyltransferase (DNMT)3a and DNMT3b were increased in curcumin-treated cells. Collectively, these results indicate that curcumin serves a role in the epigenetic regulation of mTOR expression, and that mTOR downregulation is due to promoter hypermethylation, which may be associated with DNMT3a and DNMT3b upregulation. The results of the present study contribute towards improving the understanding of curcumin treatment in multiple myeloma and provide novel insights into the molecular mechanisms underlying the epigenetic regulation of mTOR.

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

“…However, with regard to multiple myeloma cells, it has recently been reported that curcumin-induced promoter methylation to the mTOR gene was associated with a corresponding downregulation of its expression. The authors suggested that curcumin-induced hypermethylation of mTOR may be associated with the upregulation of DNMT3a and DNMT3b (47). Here, we found that curcumin downregulated TET1 in T47D and upregulated DNMT3a and DNMT3b in T47D and HCC-38 cells.…”

Natural Products Impacting DNA Methyltransferases and Histone Deacetylases

“…However, curcumin is known as a PAINS (pan-assay interference compounds) and thus its bioactivities have to be analyzed with care ( Nelson et al, 2017 ). A recent report indicated an inhibition of the growth of myeloma cells by curcumin with an IC 50 value of 10 µM ( Chen et al, 2019a ). Curcumin has been reported to induce cell cycle arrest at G1/S phase in androgen-sensitive prostate cancer LNCaP cells and androgen insensitive PC-3 cells ( Srivastava et al, 2007 ).…”

Target of Rapamycin Regulates Genome Methylation Reprogramming to Control Plant Growth in Arabidopsis

“…Methylation level of CMT2 was decreased in AZD + RAP treated sample, implying that TOR inhibition may activate DRM2 or CMT2 to maintain CHH methylation level. Interestingly, our study showed that TOR regulated genome DNA methylation to control plant growth in Arabidopsis, while curcumin induced the promoter hypermethylation of mTOR gene in myeloma cells (Chen et al, 2019), suggesting that TOR had a feedback regulation mechanism in the process of regulating DNA methylation. The detailed regulatory mechanisms of TOR and DNA methyltransferases still need further study in the future.…”