The TGF-β-induced up-regulation of NKG2DLs requires AKT/GSK-3β-mediated stabilization of SP1.
Natural killer (NK) cells play an important role in preventing cancer development. NK group 2 member D (NKG2D) is an activating receptor expressed in the membrane of NK cells. Tumour cells expressing NKG2DL become susceptible to an immune-dependent rejection mainly mediated by NK cells. The paradoxical roles of transforming growth factor beta (TGF-β) in regulation of NKG2DL are presented in many studies, but the mechanism is unclear. In this study, we showed that TGF-β up-regulated the expression of NKG2DLs in both PC3 and HepG2 cells. The up-regulation of NKG2DLs was characterized by increasing the expression of UL16-binding proteins (ULBPs) 1 and 2. TGF-β treatment also increased the expression of transcription factor SP1. Knockdown of SP1 significantly attenuated TGF-β-induced up-regulation of NKG2DLs in PC3 and HepG2 cells, suggesting that SP1 plays a key role in TGF-β-induced up-regulation of NKG2DLs. TGF-β treatment rapidly increased SP1 protein expression while not mRNA level. It might be due to that TGF-β can elevate SP1 stability by activating PI3K/AKT signalling pathway, subsequently inhibiting GSK-3β activity and decreasing the association between SP1 and GSK-3β. Knockdown of GSK-3β further verified our findings. Taken together, these results revealed that AKT/GSK-3β-mediated stabilization of SP1 is required for TGF-β induced up-regulation of NKG2DLs. Our study provided valuable evidence for exploring the tumour immune modulation function of TGF-β.
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Xiao-Hui
XH
Chen
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Lin-Lin
LL
Lu
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Hong-Peng
HP
Ke
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Zong-Cai
ZC
Liu
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Hai-Fang
HF
Wang
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Wei
W
Wei
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Yi-Fei
YF
Qi
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Hong-Sheng
HS
Wang
Department of Pharmacology, School of Pharmaceutical Sciences, Jinan University, Guangzhou, China.
Shao-Hui
SH
Cai
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Jun
J
Du
D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D055630:Receptors, NK Cell Lectin-Like / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
D055630:Receptors, NK Cell Lectin-Like; D016329:Sp1 Transcription Factor; D016212:Transforming Growth Factor beta; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt
NK cells; NK group 2 member D; SP1; cancer; transforming growth factor beta