Abstract
Activating transcription factor 3 (ATF3), a transcription factor and acute stress sensor, is rapidly induced by a variety of pathophysiological signals and is essential in the complex processes in cellular stress response. FOXP3, a well-known breast and prostate tumor suppressor from the X chromosome, is a novel transcriptional repressor for several oncogenes. However, it remains unknown whether ATF3 is the target protein of FOXP3. Herein, we demonstrate that ATF3 expression is regulated by FOXP3. Firstly, we observed that overexpression of FOXP3 reduced ATF3 protein level. Moreover, knockdown FOXP3 by siRNA increased ATF3 expression. Secondly, FOXP3 dose-dependently reduced ATF3 promoter activity in the luciferase reporter assay. Since FOXP3 is regulated by post-translational modifications (PTMs), we next investigated whether PTMs affect FOXP3-mediated ATF3 expression. Interestingly, we observed that phosphorylation mutation on FOXP3 (Y342F) significantly abolished FOXP3-mediated ATF3 expression. However, other PTM mutations on FOXP3, including S418 phosphorylation, K263 acetylation and ubiquitination, and K268 acetylation and ubiquitination, did not alter FOXP3-mediated ATF3 expression. Finally, the FOXP3 binding site was found on ATF3 promoter region by deletion and mutagenesis analysis. Taken together, our results suggest that FOXP3 functions as a novel regulator of ATF3 and that this novel event may be involved in tumor development and progression.
Highlights
Since Forkhead Box Protein P3 (FOXP3) is a transcription factor, we first investigated the role of FOXP3 on Activating transcription factor 3 (ATF3) expression
We demonstrated that replacement of Y342 by a phenylalanine (F) residue in FOXP3 leads to significant loss of the repression of ATF3’s transcriptional activity
A previous study has shown that phosphorylation at Y342 of FOXP3 by lymphocyte-specific protein tyrosine kinase (LCK) represses cell invasion [48], suggesting that phosphorylation at Y342 of FOXP3 by LCK plays an important role for ATF3 expression
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. CD274 (PD-L1) expression is inversely associated with FOXP3+ cell density in colorectal cancer tissues [23] and FOXP3 is expressed significantly higher in cytolytic-high colorectal tumors [24] Together, these results demonstrate that FOXP3 has broad functions as a tumor suppressor in breast and prostate cancers and a tumor promoter in non-small cell lung cancer, suggesting that the regulatory machinery associating with FOXP3 in each cancer type might be critical for FOXP3 function. Our group is the first to demonstrate that SUMOylation of ATF3 alters its transcriptional activity on regulation of TP53 gene [33], and that loss of SUMOylation on ATF3 inhibits proliferation of prostate cancer cells by modulating CCND1/2 activity [34] These results imply that ATF3 has broad biological and physiological functions including cancer development and metabolism. Since FOXP3 is a transcription factor and has broad biological and physiological effects in cells and organs, we assessed the function of FOXP3 in ATF3 transcriptional activity using several human cell lines in the present study
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