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.
This work was supported by National Natural Science Foundation of China Grants 91029736, 9162910, and 91442111, Israel Science Foundation–National Natural Science Foundation of China Program Grant 31461143010, Ministry of Science and Technology Grant 2008AA02Z129 (Program 863), National Key Research and Development Program of China Grant 2016YFC1303604, Program for Changjiang Scholars and Innovative Research Team in University Grant IRT13023, and by funding from the State Key Laboratory of Medicinal Chemical Biology.
The sequences presented in this article have been submitted to the Gene Expression Omnibus under accession number GSE92303.
The online version of this article contains supplemental material.
Abbreviation used in this article:
- arginase 1
- bone marrow cell
- bone marrow–derived myeloid-derived suppressor cell
- histone deacetylase
- inducible NO synthase
- myeloid-derived suppressor cell
- mass spectrometry
- small interfering RNA
- TNFR-associated factor.
- Received October 5, 2016.
- Accepted January 20, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.