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JMJD6 is a possible epigenetic regulator of PD-L1 expression and an independent favorable prognostic factor of intrahepatic cholangiocarcinoma

ABSTRACT: Association of Jumonji domain-containing 6 (JMJD6) with outcomes of various cancers has been shown, however the impact on intrahepatic cholangiocarcinoma (ICC) has never been reported yet. The aim of this study is to clarify the role of JMJD6 in the clinical settings and the impact on the outcomes of ICC. The resected liver specimens of 53 patients who underwent surgery for ICC were analyzed for JMJD6 expression by immunohistochemistry staining. The relationship between clinicopathological factors and the JMJD6 expression was investigated. Commercial culture cell lines derived from primary ICC were incubated with siRNA to decrease the expression of JMJD6. The RNA and protein were extracted to analyze the downstream gene expression with RNA-sequence and western blotting. The relationship between JMJD6 expression and tumor immunological factors were evaluated. Low expression of JMJD6 was significantly associated with poor overall survival (OS, p=0.0024). The further analyses revealed that the higher expression of JMJD6 was one of the independent better prognostic factors. ICC cells with JMJD6 knockdown revealed significantly higher programmed death-ligand 1 (PD-L1) expression (p=0.0410) in RNA-seq. The western blotting showed the result matching with the RNA-seq. H3K4me3 histone protein expression was also upregulated under the knockdown of JMJD6. A higher CD8+ T cell count combined with high expression of JMJD6 was one of the significant indicators of better prognosis both in PFS and OS. In vitro experiments proved that JMJD6 regulated the expression of PD-L1 and the paired evaluation of JMJD6 and the immune status was one of the useful factors to stratify the prognosis of ICC. Our results suggest that JMJD6 could influence the prognosis of ICC through the epigenetic regulation of PD-L1 expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171974 | GEO | 2022/03/23

REPOSITORIES: GEO

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Project description:PD-L1 Inhibitor Regulates the miR-33a-5p/PTEN Signaling Pathway and Can Be Targeted to Sensitize Glioblastomas to Radiation. Glioblastoma (GBM) is the most common and lethal brain tumor in adults. Ionizing radiation (IR) is a standard treatment for GBM patients and results in DNA damage. However, the clinical efficacy of IR is limited due to therapeutic resistance. The programmed death ligand 1 (PD-L1) blockade has a shown the potential to increase the efficacy of radiotherapy by inhibiting DNA damage and repair responses. The miR-33a-5p is an essential microRNA that promotes GBM growth and self-renewal. In this study, we investigated whether a PD-L1 inhibitor (a small molecule inhibitor) exerted radio-sensitive effects to impart an anti-tumor function in GBM cells by modulating miR-33a-5p. U87 MG cells and U251 cells were pretreated with PD-L1 inhibitor. The PD-L1 inhibitor-induced radio-sensitivity in these cells was assessed by assaying cellular apoptosis, clonogenic survival assays, and migration. TargetScan and luciferase assay showed that miR-33a-5p targeted the phosphatase and tensin homolog (PTEN) 3' untranslated region. The expression level of PTEN was measured by western blotting, and was also silenced using small interfering RNAs. The levels of DNA damage following radiation was measured by the presence of γ-H2AX foci, cell cycle, and the mRNA of the DNA damage-related genes, BRCA1, NBS1, RAD50, and MRE11. Our results demonstrated that the PD-L1 inhibitor significantly decreased the expression of the target gene, miR-33a-5p. In addition, pretreatment of U87 MG and U251 cells with the PD-L1 inhibitor increased radio-sensitivity, as indicated by increased apoptosis, while decreased survival and migration of GBM cells. Mir-33a-5p overexpression or silencing PTEN in U87 MG and U251 cells significantly attenuated PD-L1 radiosensitive effect. Additionally, PD-L1 inhibitor treatment suppressed the expression of the DNA damage response-related genes, BRCA1, NBS1, RAD50, and MRE11. Our results demonstrated a novel role for the PD-L1 inhibitor in inducing radio- sensitivity in GBM cells, where inhibiting miR-33a-5p, leading to PTEN activated, and inducing DNA damage was crucial for antitumor immunotherapies to treat GBM.

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JMJD6 is a possible epigenetic regulator of PD-L1 expression and an independent favorable prognostic factor of intrahepatic cholangiocarcinoma

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