EGFR‐ERK pathway regulates CSN6 to contribute to PD‐L1 expression in glioblastoma

Su, Lingrui; Guo, Wenli; Lou, Lei; Nie, Saisai; Zhang, Qing; Liu, Ying; Chang, Ying; Zhang, Xianghong; Li, Yuehong; Shen, Haitao

doi:10.1002/mc.23176

Cited by 28 publications

(21 citation statements)

References 43 publications

(110 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hyperactivation of EGFR in HCC is suggested to be associated with aggressive tumors, metastasis, and poor patient survival (Berasain and Avila, 2014;Lanaya et al, 2014). 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). Therefore, this raise the possibility that EGF/EGFR signal is also attributable to the upregulation of PD-L1 in HCC.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

View full text Add to dashboard Cite

show abstract

“…ERK signaling has also been shown to regulate PD-L1-associated GBM cell malignancy and aggressiveness [70]. It has also been reported that the activation of ERK signaling inhibits the degradation of PD-L1 and maintains stability of PD-L1 in GBM [71]. In a clinicopathological analysis, STAT3, ERK, and PD-L1 are associated with the progression of dermatofibrosarcoma protuberans [72].…”

Section: Discussionmentioning

confidence: 97%

Paliperidone Inhibits Glioblastoma Growth in Mouse Brain Tumor Model and Reduces PD-L1 Expression

Liu

Huang

Lin

et al. 2021

Cancers

View full text Add to dashboard Cite

A previous study from our group reported that monocyte adhesion to glioblastoma (GBM) promoted tumor growth and invasion activity and increased tumor-associated macrophages (TAMs) proliferation and inflammatory mediator secretion as well. The present study showed that prescribed psychotropic medicine paliperidone reduced GBM growth and immune checkpoint protein programmed death ligand (PD-L)1 expression and increased survival in an intracranial xenograft mouse model. An analysis of the database of patients with glioma showed that the levels of PD-L1 and dopamine receptor D (DRD)2 were higher in the GBM group than in the low grade astrocytoma and non-tumor groups. In addition, GFP expressing GBM (GBM-GFP) cells co-cultured with monocytes-differentiated macrophage enhanced PD-L1 expression in GBM cells. The enhancement of PD-L1 in GBM was antagonized by paliperidone and risperidone as well as DRD2 selective inhibitor L741426. The expression of CD206 (M2 phenotype marker) was observed to be markedly increased in bone marrow-derived macrophages (BMDMs) co-cultured with GBM. Importantly, treatment with paliperidone effectively decreased CD206 and also dramatically increased CD80 (M1 phenotype marker) in BMDMs. We have previously established a PD-L1 GBM-GFP cell line that stably expresses PD-L1. Experiments showed that the expressions of CD206 was increased and CD80 was mildly decreased in the BMDMs co-cultured with PD-L1 GBM-GFP cells. On the other hands, knockdown of DRD2 expression in GBM cells dramatically decreased the expression of CD206 but markedly increased CD80 expressions in BMDMs. The present study suggests that DRD2 may be involved in regulating the PD-L1 expression in GBM and the microenvironment of GBM. Our results provide a valuable therapeutic strategy and indicate that treatments combining DRD2 antagonist paliperidone with standard immunotherapy may be beneficial for GBM treatment.

show abstract

“…found that loss of the phosphatase and tensin homolog (PTEN) and consequential activation of the PI3K/AKT pathway increased the expression of PD-L1 in glioma. Recently, their finding has been expanded with a role for the EGFR-Ras-MAPK signaling pathway by upregulation of COP9 signalosome complex subunit six (CSN6) and subsequent stabilization of PD-L1 in gliomas (52). In non-small-cell lung carcinoma, EGFR-activating mutations were significantly associated with increased PD-L1 expression that could be downregulated by treatment with erlotinib (17,18).…”

Section: Discussionmentioning

confidence: 99%

Oxygen Deprivation Modulates EGFR and PD-L1 in Squamous Cell Carcinomas of the Head and Neck

et al. 2021

View full text Add to dashboard Cite

Abundance and signaling of the epidermal growth factor receptor (EGFR) and programmed cell death protein ligand 1 (PD-L1) in head and neck squamous cell carcinoma (HNSCC) are not only genetically determined but are also subject to the traits of the tumor microenvironment, which has hitherto not been clarified completely. We investigated the impact of hypoxia on the EGFR system and on PD-L1 in six HPV negative HNSCC cell lines in vitro and in FaDu xenografts in vivo. Protein levels of EGFR, AKT, pAKT, ERK1/2, pERK1/2, CA IX, cleaved PARP (apoptosis), LC3B (autophagy), and PD-L1 were quantified by western blot after oxygen deprivation or CoCl2, staurosporine, and erlotinib treatment. In FaDu xenograft tumors the expression of EGFR, CA IX andCD34 staining were analyzed. Reduced oxygen supply strongly downregulated EGFR protein levels and signaling in FaDu cells in vitro and in vivo, and a transient downregulation of EGFR signaling was found in three other HNSCC cell lines. PD-L1 was affected by oxygen deprivation in only one HNSCC cell line showing increased protein amounts. The results of this study indicate a significant impact of the traits of the tumor microenvironment on crucial molecular targets of cancer therapies with high clinical relevance for therapy resistance and response in HNSCC.

show abstract

EGFR‐ERK pathway regulates CSN6 to contribute to PD‐L1 expression in glioblastoma

Cited by 28 publications

References 43 publications

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

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

Paliperidone Inhibits Glioblastoma Growth in Mouse Brain Tumor Model and Reduces PD-L1 Expression

Oxygen Deprivation Modulates EGFR and PD-L1 in Squamous Cell Carcinomas of the Head and Neck

Contact Info

Product

Resources

About