Due to lack of estrogen receptor α (ERα, gene name: ESR1), ERα-negative breast carcinoma is insensitive to endocrine therapy, and restoration of ERα has become a promising strategy for ERα-negative breast cancer treatment. Sesamol, a naturally occurring phenolic compound, is usually extracted from sesame seeds. Previous investigations have unmasked its antioxidant and anti-inflammation properties. In this study, sesamol induced ERα functional re-expression followed by upregulation of its downstream pS2 and GREB1 genes in ERα-negative breast carcinoma. Moreover, it endowed responsiveness of ERα-negative breast carcinoma to the endocrine treatment drug 4-hydroxytamoxifen without influencing the viability of normal human umbilical vein endothelial cells. Mechanistically, sesamol induced ESR1 gene promoter demethylation by downregulating the expression of the DNA methyltransferases DNMT3A and DNMT3B, without affecting DNMT1. Moreover, the non-coding RNA miR-370-3p directly targeted DNMT3A and DNMT3B mRNA, and its expression increased upon treatment with sesamol. Artificial abrogation of miR-370-3p expression with an antagomir abolished the inhibition of DNMT3A and DNMT3B expression by sesamol, resulting in a fallback in ERα reactivation. In mice, sesamol significantly induced ERα re-expression via miR-370-3p-mediated downregulation of DNMT3A and DNMT3B. Sesamol may be a safe and effective option for clinical adjuvant therapy in patients with ERα-negative breast cancer.

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