The
transcription factor forkhead box P3 (FOXP3) is a
biomarker for regulatory T cells and can also be expressed in
cancer cells, but its function in
cancer appears to be divergent. The role of hepatocyte-expressed FOXP3 in
hepatocellular carcinoma (HCC) is unknown. Here, we collected
tumor samples and clinical information from 115 HCC patients and used five human
cancer cell lines. We examined FOXP3
mRNA sequences for mutations, used a
luciferase assay to assess promoter activities of FOXP3's target genes, and employed mouse
tumor models to confirm in vitro results. We detected mutations in the FKH domain of FOXP3 mRNAs in 33% of the HCC
tumor tissues, but in none of the adjacent nontumor tissues. None of the mutations occurred at high frequency, indicating that they occurred randomly. Notably, the mutations were not detected in the corresponding regions of FOXP3 genomic
DNA, and many of them resulted in amino acid substitutions in the FKH region, altering FOXP3's subcellular localization. FOXP3 delocalization from the nucleus to the cytoplasm caused loss of transcriptional regulation of its target genes, inactivated its
tumor-inhibitory capability, and changed cellular responses to
histone deacetylase (
HDAC) inhibitors. More complex FKH mutations appeared to be associated with worse prognosis in HCC patients. We conclude that mutations in the FKH domain of FOXP3
mRNA frequently occur in HCC and that these mutations are caused by errors in transcription and are not derived from genomic
DNA mutations. Our results suggest that transcriptional mutagenesis of FOXP3 plays a role in HCC.