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Tytuł pozycji:

PKM2-Induced the Phosphorylation of Histone H3 Contributes to EGF-Mediated PD-L1 Transcription in HCC

Tytuł:
PKM2-Induced the Phosphorylation of Histone H3 Contributes to EGF-Mediated PD-L1 Transcription in HCC
Autorzy:
Xiao Wang
Chao Liang
Xin Yao
Ruo-Han Yang
Zhan-Sheng Zhang
Fan-Ye Liu
Wen-Qi Li
Shu-Hua Pei
Jing Ma
Song-Qiang Xie
Dong Fang
Temat:
epidermal growth factor
Pyruvate kinase isoform M2
histone H3
programmed death-ligand-1
hepatocellular carcinoma
Therapeutics. Pharmacology
RM1-950
Źródło:
Frontiers in Pharmacology, Vol 11 (2020)
Wydawca:
Frontiers Media S.A., 2020.
Rok publikacji:
2020
Kolekcja:
LCC:Therapeutics. Pharmacology
Typ dokumentu:
article
Opis pliku:
electronic resource
Język:
English
ISSN:
1663-9812
Relacje:
https://www.frontiersin.org/articles/10.3389/fphar.2020.577108/full; https://doaj.org/toc/1663-9812
DOI:
10.3389/fphar.2020.577108
Dostęp URL:
https://doaj.org/article/cb089488408d49b9882f1d78864fce8e  Link otwiera się w nowym oknie
Numer akcesji:
edsdoj.b089488408d49b9882f1d78864fce8e
Czasopismo naukowe
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.

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