KDM2A interacts with estrogen receptor α to promote bisphenol A and S-induced breast cancer cell proliferation by repressing TET2 expression

As a recognized endocrine disruptor in the environment targeting estrogen receptors (ERs), Bisphenol A (BPA) and its bisphenol S (BPS) analogs are involved in the development of breast cancer. Epigenetic modifications are crucial in many biological processes, and DNA hydroxymethylation (DNAhm) coupled with histone methylation is implicated in epigenetic machinery covering cancer occurrence. Our previous study indicated that BPA/BPS induces breast cancer cell (BCC) proliferation with enhanced estrogenic transcriptional activity and causes the change of DNAhm depending on ten-eleven translocation 2 (TET2) dioxygenase. Herein, we investigated the interplay of KDM2A-mediated histone demethylation with ER-dependent estrogenic activity (EA) and identified their function in DNAhm catalyzed by TET2 for ER-positive (ER+) BCC proliferation induced by BPA/BPS. We found that BPA/BPS-treated ER+ BCCs presented increased KDM2A mRNA and protein levels but reduced TET2 and genomic DNAhm. Furthermore, KDM2A promoted H3K36me2 loss and suppressed TET2-dependent DNAhm by reducing its chromatin binding during BPA/BPS-induced cell proliferation. Results of Co-IP & ChIP assays suggested the direct interplay of KDM2A with ER & alpha; in multiple manners. KDM2A reduced the lysine methylation of ER & alpha; protein to increase its phosphorylated activation. On the other hand, ER & alpha; did not affect KDM2A expression, while KDM2A protein levels decreased after ER & alpha; deletion, indicating that ER & alpha; binding might maintain KDM2A protein stability. In conclusion, a potential feedback circuit of KDM2A/ER & alpha;-TET2-DNAhm was identified among ER+ BCCs with significant effects on regulating BPA/BPS-induced cell proliferation. These insights advanced the understanding of the relationship between histone methylation, DNAhm, and cancer cell proliferation with EA attributed to BPA/BPS exposure in the environment.

Automated summary

BPA and BPS, recognized endocrine disruptors, target estrogen receptors and contribute to the development of breast cancer. This study reveals the interplay between KDM2A-mediated histone demethylation and ER-dependent estrogen activity, as well as their involvement in TET2-catalyzed DNA hydroxymethylation, in the proliferation of ER+ breast cancer cells induced by BPA/BPS.