Abstract
High expression of programmed death-ligand-1 (PD-L1) in hepatocellular carcinoma (HCC) cells usually inhibits the proliferation and functions of T cells, leading to immune suppression in tumor microenvironment. However, very little has been described regarding the mechanism of PD-L1 overexpression in HCC cells. In the present study, we found epidermal growth factor (EGF) stimulation promoted the expression of PD-L1 mRNA and protein in HCC cells. Inhibition of epidermal growth factor receptor (EGFR) could reverse EGF-induced the expression of PD-L1 mRNA and protein. Subsequently, we also observed that the phosphorylation level of Pyruvate kinase isoform M2 (PKM2) at Ser37 site was also increased in response to EGF stimulation. Expression of a phosphorylation-mimic PKM2 S37D mutant stimulated PD-L1 expression as well as H3-Thr11 phosphorylation in HCC cells, while inhibition of PKM2 significantly blocked EGF-induced PD-L1 expression and H3-Thr11 phosphorylation. Furthermore, mutation of Thr11 of histone H3 into alanine abrogated EGF-induced mRNA and protein expression of PD-L1, Chromatin immunoprecipitation (ChIP) assay also suggested that EGF treatment resulted in enhanced H3-Thr11 phosphorylation at the PD-L1 promoter. In a diethylnitrosamine (DEN)-induced rat model of HCC, we found that the expression of phosphorylated EGFR, PKM2 nuclear expression, H3-Thr11 phosphorylation as well as PD-L1 mRNA and protein was higher in the livers than that in normal rat livers. Taken together, our study suggested that PKM2-dependent histone H3-Thr11 phosphorylation was crucial for EGF-induced PD-L1 expression at transcriptional level in HCC. These findings may provide an alternative target for the treatment of hepatocellular carcinoma.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with a high mortality rate (Du et al, 2016; Nie et al, 2018)
Through real time PCR, we found that epidermal growth factor (EGF) promoted the mRNA expression of programmed death-ligand-1 (PD-L1) in these cancer cells (Figure 1A)
To investigate whether EGF-induced H3 Thr11 phosphorylation depended on Pyruvate kinase isoform M2 (PKM2), we examined the effects of epidermal growth factor receptor (EGFR) inhibitor Gefitinib and PKM2 inhibitor shikonin on EGF-induced H3 Thr11 phosphorylation
Summary
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with a high mortality rate (Du et al, 2016; Nie et al, 2018). Numerous studies have showed that EGF/EGFR signal could increase PD-L1 expressions in non-small-cell lung cancer, colon cancer stem cells, renal cancer cells and glioblastoma (Li et al, 2018b; Chen et al, 2019b; Ma et al, 2020; Su et al, 2020). This raise the possibility that EGF/EGFR signal is attributable to the upregulation of PD-L1 in HCC
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