Soy isoflavone metabolite equol inhibits cancer cell proliferation in a PAP associated domain containing 5-dependent and an estrogen receptor-independent manner

• DOI: 10.1016/j.jnutbio.2021.108910
• Publication Date: 2021-11-18T16:38:23Z
• Authors: Shuya Yamashita; Ichian Lin; Chihiro Oka; Motofumi Kumazoe; Satomi Komatsu; Motoki Murata; Shoko Kamachi; Hirofumi Tachibana
• Keywords: 0301 basic medicine; Estrogen Receptor alpha; Melanoma, Experimental; RNA Nucleotidyltransferases; Isoflavones; 3. Good health; MicroRNAs; 03 medical and health sciences; Equol; Receptors, Estrogen; Cell Line, Tumor; MCF-7 Cells; Humans; RNA, Small Nucleolar; Neoplasm Transplantation; Cell Proliferation; HeLa Cells

Isoflavone is a species of polyphenol found mainly in soy and soy products. Many studies have demonstrated its estrogen receptor (ER)-dependent action. Equol is an intestinal metabolite of a major soy isoflavone daidzein. We aimed to elucidate the mechanism for ER-independent actions of equol. Equol has been shown to inhibit proliferation of HeLa human cervical cancer cells and mouse melanoma B16 cells in an ER-independent manner. Using functional genetic screening, PAP associated domain containing 5 (PAPD5), which is a non-canonical poly(A) polymerase, was identified as an essential molecule in the ER-independent action. While peroral administration of equol inhibited tumor growth of control B16 cells subcutaneously inoculated in mice, it had little effect on the growth of PAPD5-ablated B16 cells. Intriguingly, equol progressed tumor growth of the PAPD5-ablated human breast cancer MCF-7 cells, which have high ERα expression. Equol has been found to induce polyadenylation of snoRNAs in a PAPD5-depdendent manner. Furthermore, peroral equol administration increased microRNA miR-320a expression in tumors. Together, these results suggest that equol may have a dual effect on ER-positive cancer cells, acting with, antiproliferative activity through PAPD5 and exhibiting proliferative activity via ERα and the former could be associated with miR-320a.