Bisphenol-A and diethylstilbestrol exposure induces the expression of breast cancer associated long noncoding RNA HOTAIR in vitro and in vivo
2014 Study Abstract
Antisense transcript, long non-coding RNA HOTAIR is a key player in gene silencing and breast cancer and is transcriptionally regulated by estradiol. Here, we have investigated if HOTAIR expression is misregulated by bisphenol-A (BPA) and diethylstilbestrol (DES). Our findings demonstrate BPA and DES induce HOTAIR expression in cultured human breast cancer cells (MCF7) as well as in vivo in the mammary glands of rat. Luciferase assay showed that HOTAIR promoter estrogen-response-elements (EREs) are induced by BPA and DES. Estrogen-receptors (ERs) and ER-coregulators such as MLL-histone methylases (MLL1 and MLL3) bind to the HOTAIR promoter EREs in the presence of BPA and DES, modify chromatin (histone methylation and acetylation) and lead to gene activation. Knockdown of ERs down-regulated the BPA and DES induced expression of HOTAIR. In summary, our results demonstrate that BPA and DES exposure alters the epigenetic programming of the HOTAIR promoters leading to its endocrine disruption in vitro and in vivo.
It is important to note that, HOTAIR is an antisense transcript and lncRNA. Therefore, our studies also demonstrate that endocrine disruptors can disrupt the noncoding RNAs and can induce antisense transcripts, in a similar fashion as protein coding genes from the sense strands. Our studies revealed novel epigenetic mechanism of endocrine disruption, novel roles of MLL histone methylases and their coordination with ERs and various ER-coregulators during endocrine disruption, both in vitro and in vivo. Although further in vivo analyses are required to understand the detailed mechanism of HOTAIR gene expression and misregulation by EDCs, synthetics estrogens, and other environmental toxins/chemical, our observations indicate that exposure to BPA or DES may turn on the expression of HOTAIR in vivo, in a very similar fashion to estrogen even in the absence of estrogen, and that may result in adverse health effects including cancer and other hormonally regulated disorders.
- Full study (free access) : Bisphenol-A and diethylstilbestrol exposure induces the expression of breast cancer associated long noncoding RNA HOTAIR in vitro and in vivo, The Journal of steroid biochemistry and molecular biology, NCBI PubMed PMC4025971, 2014.
- Featured image : Models showing the roles of ERs, MLLs and other ER-coregulators during BPA and DES mediated endocrine disruption of HOTAIR. PMC4025971/figure/F7.