Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.
Cell Signal. 2013 Jun;25(6):1476-85. doi: 10.1016/j.cellsig.2013.03.015. Epub 2013 Mar 23.
Retinoic acid (RA) has been used as a chemopreventive agent for breast cancer. It has been shown that HOXA5 is a critical mediator of RA-induced cell growth inhibition. However, the molecular mechanisms underlying RA-induced HOXA5 expression remain largely unknown. Here we report that in addition to transcriptional regulation, post-transcriptional regulation also contributes to RA-induced HOXA5 expression. miR-130a, a c-Myc responsive miRNA, represses HOXA5 cellular levels under unstressed condition. Upon RA treatment, c-Myc is quickly degraded via the proteasome-dependent pathway. This in turn decreases miR-130a levels and de-represses the translation of HOXA5. We also show that the de-repression of HOXA5 translation is dependent on the RNA-binding protein Human antigen R (HuR), which binds to 3'UTR of HOXA5 mRNA and increases its stability in response to RA treatment. Collectively, these results demonstrate that HuR and miR-130a dynamically regulate HOXA5 gene expression via modulating HOXA5 mRNA turnover and translation, respectively, thereby contributing to RA-induced growth inhibition.
维甲酸（RA）已被用作乳腺癌的化学预防剂。已经表明，HOXA5 是 RA 诱导的细胞生长抑制的关键介质。然而，RA 诱导 HOXA5 表达的分子机制在很大程度上仍然未知。在这里，我们报告除了转录调控外，转录后调控也有助于 RA 诱导的 HOXA5 表达。miR-130a 是一种 c-Myc 反应性 miRNA，在未受应激的情况下抑制 HOXA5 的细胞水平。在 RA 处理后，c-Myc 通过蛋白酶体依赖性途径迅速降解。这反过来又降低了 miR-130a 的水平，并解除了 HOXA5 的翻译抑制。我们还表明，HOXA5 翻译的去抑制依赖于 RNA 结合蛋白 Human antigen R（HuR），HuR 结合到 HOXA5 mRNA 的 3'UTR 上，并响应 RA 处理增加其稳定性。总之，这些结果表明 HuR 和 miR-130a 通过分别调节 HOXA5 mRNA 的周转和翻译来动态调节 HOXA5 基因表达，从而有助于 RA 诱导的生长抑制。
