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

## TL;DR

Arid4a suppresses breast cancer metastasis by stabilizing mRNAs of metastasis-suppressing genes like MTSS1, suggesting it could be a new therapeutic target.

## Contribution

Arid4a's novel role in stabilizing metastasis-suppressing mRNAs via 3′UTR stem-loop binding is newly identified.

## Key findings

- Low Arid4a expression correlates with poor breast cancer prognosis.
- Arid4a stabilizes mRNAs of MTSS1, TIMP2, Rb1, and PTEN to inhibit metastasis.
- Arid4a's Arid domain is essential for mRNA stabilization and metastasis suppression.

## Abstract

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.

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.

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.

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.

Here, we identified the low expression pattern of RNA‐binding protein Arid4a in human breast cancers and its potential role in modulating tumor metastasis‐related gene expression and tumor progression. Mechanistically, Arid4a could upregulate the expression of metastasis‐suppressing genes by stabilizing their mRNAs via binding to the stem–loop structure localized in 3′ UTR.