Arid4a Suppresses Breast Tumor Metastasis by Enhancing MTSS1 Expression via mRNA Stability

Background: Tumor metastasis is one of the main causes of death in cancer patients; however, the mechanism controlling metastasis is unclear. The posttranscriptional regulation of metastasis-related genes mediated by AT-rich interactive domain-containing protein 4A (Arid4a), an RNA-binding protein (RBP), has not been elucidated. Methods: Bioinformatic analysis, qRT-PCR, immunohistochemistry, and immunoblotting were employed to determine the expression of Arid4a in breast tumor tissues and its association with the survival of cancer patients. In vitro and in vivo cellular experiments were used to assess the function of Arid4a in breast tumor metastasis. PCR array, RNA immunoprecipitation (RIP), luciferase, mRNA stability, RIP-ChIP, and EMSA were conducted to elucidate the potential mechanism of Arid4a. Results: Reduced expression of Arid4a in breast tumor samples was detected via bioinformatic analyses and experimental methods. Low Arid4a expression was significantly correlated with poor prognosis in breast cancer patients. Gain-of-function and silencing experiments confirmed the inhibitory effect of Arid4a on tumor metastasis in vitro and in vivo. Mechanistically, Arid4a preferentially stabilizes metastasis-suppressing transcripts, including metastasis suppressor 1 (MTSS1), tissue inhibitor of metalloproteinase 2 (TIMP2), retinoblastoma 1 (Rb1), and phosphatase and tensin homolog (PTEN), through binding to a conserved structural RNA element localized in the 3 ' untranslated region (3 ' UTR). The Arid domain of Arid4a is required for its mRNA stabilization and metastasis inhibition. Notably, the expression of Arid4a and metastasis-suppressing genes was positively correlated in human breast tumor tissues. Conclusions: Arid4a was confirmed to suppress breast tumor metastasis progression by stabilizing the transcripts of tumor metastasis-suppressing genes, suggesting that Arid4a might be a potential therapeutic target for breast cancer treatment.