Edited by Xiao-Fan WangAutotaxin (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 (3UTR). The RNA-binding proteins HuR and AUF1 directly bound to the ATX mRNA 3UTR 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.

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Autotaxin (ATX), a vital enzyme that generates lysophosphatidic acid (LPA), affects many biological processes, including tumorigenesis, via the ATX–LPA axis. In this study, we demonstrate that microRNA‐101‐3p (miR‐101‐3p), a well‐known tumor suppressor, downregulates ATX expression at the posttranscriptional level. We found that miR‐101‐3p inhibits ATX regulation by directly targeting a conserved sequence in the ATX mRNA 3′UTR. Moreover, we observed an inverse correlation between ATX and miR‐101‐3p levels in various types of cancer cells. ATX is highly expressed in several human cancers. Here, we verified that ATX expression is significantly inhibited by miR‐101‐3p in U87 and HCT116 cells. ATX downregulation contributed to the suppression of migration, invasion, and proliferation mediated by miR‐101‐3p; furthermore, the tumor‐suppressing activity of miR‐101‐3p was partially reduced by the addition of LPA in U87 cells. Our data suggest that ATX is a novel target of miR‐101‐3p.

Autotaxin (ATX) or ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) is a secretory glycoprotein and functions as the key enzyme for lysophosphatidic acid generation. The mechanism of ATX protein trafficking is largely unknown. Here, we demonstrated that p23, a member of the p24 protein family, was the protein-sorting receptor required for endoplasmic reticulum (ER) export of ATX. A di-phenylalanine (Phe-838/Phe-839) motif in the human ATX C-terminal region was identified as a transport signal essential for the ATX-p23 interaction. Knockdown of individual Sec24 isoforms by siRNA revealed that ER export of ATX was impaired only if Sec24C was down-regulated. These results suggest that ATX is selectively exported from the ER through a p23, Sec24C-dependent pathway. In addition, it was found that AKT signaling played a role in ATX secretion regulation to facilitate ATX ER export by enhancing the nuclear factor of activated T cell-mediated p23 expression. Furthermore, the di-hydrophobic amino acid motifs (FY) also existed in the C-terminal regions of human ENPP1 and ENPP3. Such a p23, Sec24C-dependent selective ER export mechanism is conserved among these ENPP family members.

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