Estrogen receptor alpha (ERα) regulates PARN-mediated nuclear deadenylation and gene expression in breast cancer cells

The estrogen signalling pathway is highly dynamic and primarily mediated by estrogen receptors (ERs) that transcriptionally regulate the expression of target genes. While transcriptional functions of ERs have been widely studied, their roles in RNA biology have not been extensively explored. Here, we reveal a novel biological role of ER alpha (ERα) in mRNA 3’ end processing in breast cancer cells, providing an alternative mechanism in regulating gene expression at the post-transcriptional level. We show that ERα activates poly(A) specific ribonuclease (PARN) deadenylase using in vitro assays, and that this activation is further increased by tumour suppressor p53, a factor involved in mRNA processing. Consistent with this, we confirm ERα-mediated activation of nuclear deadenylation by PARN in samples from MCF7 and T47D breast cancer cells that vary in expression of ERα and p53. We further show that ERα can form complex(es) with PARN and p53. Lastly, we identify and validate expression of common mRNA targets of ERα and PARN known to be involved in cell invasion, metastasis and angiogenesis, supporting the functional overlap of these factors in regulating gene expression in a transactivation-independent manner. Together, these results show a new regulatory mechanism by which ERα regulates mRNA processing and gene expression post-transcriptionally, highlighting its contribution to unique transcriptomic profiles and breast cancer progression.

雌激素信号通路（estrogen signalling pathway）具有高度动态性，主要由雌激素受体（estrogen receptors，ERs）介导，后者可转录调控靶基因的表达。尽管学界已对雌激素受体的转录功能开展了广泛研究，但它们在RNA生物学（RNA biology）中的作用尚未得到充分探索。本研究揭示了雌激素受体α（ER alpha，ERα）在乳腺癌细胞中参与mRNA 3'端加工的全新生物学功能，为转录后水平调控基因表达提供了一种新机制。我们通过体外实验证实，ERα可激活poly(A)特异性核糖核酸酶（poly(A) specific ribonuclease，PARN）的脱腺苷酸化酶活性，且抑癌蛋白p53可进一步增强这一激活过程——p53是一种参与mRNA加工的调控因子。与此一致的是，我们在ERα和p53表达存在差异的MCF7与T47D乳腺癌细胞样本中，验证了ERα介导的PARN对细胞核内脱腺苷酸化过程的激活作用。我们进一步证实，ERα可与PARN及p53形成复合物。此外，我们还鉴定并验证了已知参与细胞侵袭、转移及血管生成的ERα与PARN的共同mRNA靶基因的表达，证实了这两种因子可通过非反式激活方式在基因表达调控中发挥功能重叠的作用。综上，本研究揭示了ERα通过转录后方式调控mRNA加工与基因表达的全新调控机制，阐明了其对独特转录组谱（transcriptomic profiles）形成及乳腺癌进展的贡献。