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.
