title: Downregulation of Ezh2 methyltransferase by FOXP3: new insight of FOXP3 into chromatin remodeling?
abstract: Transcription factor FOXP3 (forkhead box P3) is found initially as a key regulator in regulatory T cells. Recently its expression has been demonstrated in some non-lymphoid normal and cancerous cells. Now FOXP3 has been proven to regulate cancer-related genes, especially suppressor genes in breast cancer. But the mechanisms by which FOXP3 regulates suppressor genes are not fully determined. In this study, we found the inverse correlation between FOXP3 and Ezh2, an enzyme for histone H3K27 trimethylation (H3K27me3) and a central epigenetic regulator in cancer. The overexpression of FOXP3 weakened Ezh2's enhancement on the mammosphere formation, cell proliferation, directional migration, and colony forming ability of T47D cells. We demonstrated that FOXP3 could downregulate Ezh2 protein level and this depended on not only the FOXP3 expression amount, but also the nuclear localization of FOXP3. More importantly, we demonstrated FOXP3 accelerated Ezh2 protein degradation through the polyubiquitination-proteasome pathway by enhancing the transcription of E3 ligase Praja1 directly. These results provided a new mechanism for FOXP3 in histone modifications as an Ezh2 suppressor and supported new evidence for FOXP3 as a tumor suppressor in breast cancer.
authors.affiliation: Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China. zhushencq@gmail.com
authors.forename: Zhu
authors.initials: Z
authors.lastname: Shen
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Yang
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Eric
authors.initials: E
authors.lastname: Pier
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
authors.forename: Xichuan
authors.initials: X
authors.lastname: Yang
authors.forename: Ya
authors.initials: Y
authors.lastname: Xiong
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D003114:Colony-Forming Units Assay; D000071221:Enhancer of Zeste Homolog 2 Protein; D057890:Epigenomics; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008168:Lung / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D035683:MicroRNAs; D011506:Proteins; D012333:RNA, Messenger; D025821:Polyubiquitin; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C484661:PJA1 protein, human; C109319:Pja1 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Ezh2; FOXP3; H3K27me3; HDAC; Praja1; S-phase kinase-associated protein 2; SATB1; SKP2; Transcription; Ubiquitination; enhancer of zeste homolog 2; histone deacetylase; miR-101; microRNA-101; special AT-rich sequence binding protein 1; trimethylation of histone H3 lysine 27