The histone deacetylase inhibitor valproic acid inhibits NKG2D expression in natural killer cells through suppression of STAT3 and HDAC3.
NKG2D is a major activating receptor of NK cells and plays a critical role in tumor immunosurveillance. NKG2D expression in NK cells is inhibited by the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and enhanced by the narrow-spectrum HDAC inhibitor entinostat. We previously demonstrated that entinostat enhanced NKG2D transcription by increasing acetylation of Histones H3 and H4. However, the mechanism by which VPA reduces NKG2D expression in NK cells is not known. We have also shown that NKG2D transcription is regulated by STAT3 phosphorylation. In this study, we investigated regulation of NKG2D expression in NK cells by VPA and entinostat by assessing protein expression, phosphorylation, and interaction of HDACs and STAT3. We find that VPA selectively inhibits STAT3 tyrosine705 phosphorylation, but entinostat does not. STAT3 complexes with HDAC3, and HDAC3 inhibition represses STAT3 phosphorylation and therefore NKG2D expression. NK cells from STAT3 wild-type mice downregulate NKG2D in response to VPA, but not NK cells from STAT3 knockout mice. These results show that VPA is a potent inhibitor of STAT3 phosphorylation and demonstrate that histone acetylation and STAT3 tyrosine705 phosphorylation cooperate in regulating NKG2D expression in NK cells.
Laboratory of Integrative Medicine, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 CaiLun Rd., Shanghai 201203, P. R. China.
Lulu
L
Ni
Department of Immunology and Pathogenic Biology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 CaiLun Rd., Shanghai 201203, P. R. China.
Lixin
L
Wang
Laboratory of Integrative Medicine, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 CaiLun Rd., Shanghai 201203, P. R. China.
Chao
C
Yao
Laboratory of Integrative Medicine, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 CaiLun Rd., Shanghai 201203, P. R. China.
Zhongya
Z
Ni
Laboratory of Integrative Medicine, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 CaiLun Rd., Shanghai 201203, P. R. China.
Fei
F
Liu
Laboratory of Integrative Medicine, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 CaiLun Rd., Shanghai 201203, P. R. China.
Chenyuan
C
Gong
Laboratory of Integrative Medicine, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 CaiLun Rd., Shanghai 201203, P. R. China.
Xiaowen
X
Zhu
Laboratory of Integrative Medicine, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 CaiLun Rd., Shanghai 201203, P. R. China.
Xuewei
X
Yan
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Stephanie S
SS
Watowich
Pediatrics, Nationwide Children's Hospital, 700 Children's Drive, WA4023, Columbus, OH, 43205, USA.
Dean A
DA
Lee
Laboratory of Integrative Medicine, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 CaiLun Rd., Shanghai 201203, P. R. China.|Department of Immunology and Pathogenic Biology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 CaiLun Rd., Shanghai 201203, P. R. China.
Shiguo
S
Zhu
D000107:Acetylation; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*; D000099186:Histone Deacetylase 3
D001549:Benzamides; D006655:Histone Deacetylases; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011725:Pyridines; D050796:STAT3 Transcription Factor; D014443:Tyrosine; D014635:Valproic Acid; D000099186:Histone Deacetylase 3; C527085:KLRK1 protein, human; C494086:STAT3 protein, human; C118739:entinostat