Sun Shuhong, Zhang Xiaotian, Lyu Lin, Li Xixi, Yao Siliang, Zhang Junjie
From the Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, and.
From the Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, and
J Biol Chem. 2016 Dec 9;291(50):25823-25836. doi: 10.1074/jbc.M116.756908. Epub 2016 Oct 26.
Autotaxin (ATX) is a key enzyme that converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA), a lysophospholipid mediator that regulates cellular activities through its specific G protein-coupled receptors. The ATX-LPA axis plays an important role in various physiological and pathological processes, especially in inflammation and cancer development. Although the transcriptional regulation of ATX has been widely studied, the post-transcriptional regulation of ATX is largely unknown. In this study, we identified conserved adenylate-uridylate (AU)-rich elements in the ATX mRNA 3'-untranslated region (3'UTR). The RNA-binding proteins HuR and AUF1 directly bound to the ATX mRNA 3'UTR and had antagonistic functions in ATX expression. HuR enhanced ATX expression by increasing ATX mRNA stability, whereas AUF1 suppressed ATX expression by promoting ATX mRNA decay. HuR and AUF1 were involved in ATX regulation in Colo320 human colon cancer cells and the LPS-stimulated human monocytic THP-1 cells. HuR knockdown suppressed ATX expression in B16 mouse melanoma cells, leading to inhibition of cell migration. This effect was reversed by AUF1 knockdown to recover ATX expression or by the addition of LPA. These results suggest that the post-transcriptional regulation of ATX expression by HuR and AUF1 modulates cancer cell migration. In summary, we identified HuR and AUF1 as novel post-transcriptional regulators of ATX expression, thereby elucidating a novel mechanism regulating the ATX-LPA axis.
自分泌运动因子（ATX）是一种关键酶，可将溶血磷脂酰胆碱（LPC）转化为溶血磷脂酸（LPA），LPA是一种溶血磷脂介质，通过其特定的G蛋白偶联受体调节细胞活动。ATX-LPA轴在各种生理和病理过程中发挥重要作用，尤其是在炎症和癌症发展过程中。尽管对ATX的转录调控已进行了广泛研究，但ATX的转录后调控在很大程度上仍不清楚。在本研究中，我们在ATX mRNA的3'非翻译区（3'UTR）中鉴定出保守的富含腺苷酸-尿苷酸（AU）的元件。RNA结合蛋白HuR和AUF1直接与ATX mRNA的3'UTR结合，并在ATX表达中具有拮抗功能。HuR通过增加ATX mRNA稳定性来增强ATX表达；而AUF1则通过促进ATX mRNA降解来抑制ATX表达。HuR和AUF1参与了人结肠癌细胞Colo320和脂多糖刺激的人单核细胞THP-1细胞中ATX的调控。敲低HuR可抑制B16小鼠黑色素瘤细胞中ATX的表达，从而抑制细胞迁移。敲低AUF1以恢复ATX表达或添加LPA可逆转这种作用。这些结果表明，HuR和AUF1对ATX表达的转录后调控调节了癌细胞的迁移。总之，我们将HuR和AUF1鉴定为ATX表达的新型转录后调节因子，从而阐明了一种调节ATX-LPA轴的新机制。
