title: Epigenetic Component p66a Modulates Myeloid-Derived Suppressor Cells by Modifying STAT3.
abstract: STAT3 plays a critical role in myeloid-derived suppressor cell (MDSC) accumulation and activation. Most studies have probed underlying mechanisms of STAT3 activation. However, epigenetic events involved in STAT3 activation are poorly understood. In this study, we identified several epigenetic-associated proteins such as p66a (Gatad2a), a novel protein transcriptional repressor that might interact with STAT3 in functional MDSCs, by using immunoprecipitation and mass spectrometry. p66a could regulate the phosphorylation and ubiquitination of STAT3. Silencing p66a promoted not only phosphorylation but also K63 ubiquitination of STAT3 in the activated MDSCs. Interestingly, p66a expression was significantly suppressed by IL-6 both in vitro and in vivo during MDSC activation, suggesting that p66a is involved in IL-6-mediated differentiation of MDSCs. Indeed, silencing p66a could promote MDSC accumulation, differentiation, and activation. Tumors in mice injected with p66a small interfering RNA-transfected MDSCs also grew faster, whereas tumors in mice injected with p66a-transfected MDSCs were smaller as compared with the control. Thus, our data demonstrate that p66a may physically interact with STAT3 to suppress its activity through posttranslational modification, which reveals a novel regulatory mechanism controlling STAT3 activation during myeloid cell differentiation.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China.
authors.forename: Jiaxuan
authors.initials: J
authors.lastname: Xin
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China.
authors.forename: Zhiqian
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Su
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, United Kingdom.
authors.forename: Liyang
authors.initials: L
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China; ryang@nankai.edu.cn.|Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071, China; and.|Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin 300071, China.
authors.forename: Rongcun
authors.initials: R
authors.lastname: Yang
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D044127:Epigenesis, Genetic / Q000276:immunology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology; D055785:Gene Knockdown Techniques; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse