Detection of PD-L1 acetylation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens (human)
SUBMITTER: Naoe Nihira
PROVIDER: PXD017707 | JPOST Repository | Thu Feb 25 00:00:00 GMT 2021
REPOSITORIES: jPOST
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Project description:Fig. S1D: An in-vitro assay that identified the acetylation sites on recombinant TULP3 with the addition of recombinant human p300.
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Project description:Programmed death ligand-1 (PD-L1) is a well-known transmembrane protein, which antibodies present effective clinical therapy in multiple human cancers. However, the function of tumor cell-intrinsic PD-L1 and its related mechanism in breast cancer remains incompletely studied. Programmed death ligand 1 (PD-L1) on the membrane of tumor cells strengthens tumor immune escape. Tumor cell-intrinsic PD-L1 is also involved in tumorigenesis and development, but the mechanism in regulating PD-L1 expression remains incompletely studied. Here, we report a novel mechanism for PD-L1 that can be induced by hepatitis B X-interacting protein (HBXIP), an oncogenic transcriptional coactivator, promoting breast cancer growth. Overexpression of PD-L1 increases breast cancer proliferation in vitro and in vivo. Transcriptomic analysis also reveals that PD-L1 plays a critical role in cancer development. Furthermore, we find that the expression of PD-L1 is positively associated with HBXIP in breast cancer clinical tissues as well as in cell lines, PD-L1 and HBXIP expression have higher levels in tumor. Mechanistically, HBXIP predominantly stimulates the promoter activity of PD-L1 through coactivating transcription factor ETS2. Especially, HBXIP induced PD-L1 acetylation with the acetyltransferase p300 at lysine 270 (K270), enhancing PD-L1 protein stability. Functionally, depletion of HBXIP markedly attenuates PD-L1-induced breast tumor growth in vitro and in vivo. Moreover, aspirin decreased breast cancer growth via targeting PD-L1 and HBXIP. Taken together, our results extend a new mechanism of PD-L1 functions, expound non-immune effects of PD-L1 and imply broader uses for PD-L1 as a target in breast cancer therapy.
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Project description:PDCD1, which encodes for the PD-1 immune checkpoint receptor, is a key tumor suppressor in T cells that is recurrently inactivated in human T cell non-Hodgkin lymphomas (T-NHLs)1-3. The highest frequencies of PDCD1 deletions are detected in advanced disease, predicting inferior prognosis2. Nevertheless, the tumor-suppressive mechanisms of PD-1 signaling remain unknown. Using tractable mouse models of human T-NHL, we demonstrate that PD-1 activity in pre-malignant cells prevents cellular transformation by inhibiting the induction of rate-limiting factors for glucose uptake and conversion upon oncogenic T cell signaling. Furthermore, PD-1 negatively regulates ATP-citrate lyase (ACLY), which generates extramitochondrial acetyl-CoA for histone acetylation. Consequently, inactivation of PD-1 enables oncogene-expressing T cells to switch to glycolysis to metabolically fuel overt malignancy and unleashes ACLY activity to promote de novo histone acetylation to increase chromatin accessibility of oncogenic AP-1 transcription factors. Multimodal molecular and functional analyses of primary human T-NHL samples confirmed enforced glucose metabolism, epigenetic reprogramming, and AP-1 activation upon PDCD1 loss in patients. Thus, our results identified PD-1 as a central metabolic gatekeeper of T cell transformation and lymphoma progression and established a mechanistic link between the PD-1 checkpoint receptor and glucose-dependent histone acetylation. Together, these data uncover novel putative genotype-specific vulnerabilities in T-NHL and present a starting point for the exploration of PD-1 dependent epigenetic reprogramming in T cell biology.
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Project description:Interferon-alpha (IFNα) plays a ciritical role in immune regulation, especially in tumor microenvironment. Our previous study has demonstrated that IFNα promoted immunosuppression formation in head and neck squamous cell carcinoma. To explore the mechanism underlying IFNα-induced immunosuppression, long noncoding RNA (lncRNA) sequece was conduted. We identified a novel IFNα-induced upregulated lncRNA, lncMX1-215 in HNSCC. It was mainly located in cell nucleus. Ectopic expression of lncMX1-215 markedly inhibited IFNα-induced immunosuppression molecules, programmed cell death 1 ligand 1(PD-L1) and galectin-9 expression, and vice versa. Subsequently, histone deacetylase (HDAC) inhibitors promoted the expression of PD-L1 and galectin-9. There were binding sites of H3K27 acetylation on PD-L1 and galectin-9 promoters. Mechanically, we find that lncMX1-215 directly interacted with GCN5, a known H3K27 acetylase to interrupt its binding to H3K27 acetylation. Clinically, negative correlations between lncMX1-215 and PD-L1, galectin-9 were observed. Finally, overexpression of lncMX1-215 suppressed the proliferation and metastasis capacity in vitro and in vivo in HNSCC. Our results suggest that lncMX1-215 negatively regulates immunosuppression through interrupting GCN5/H3K27ac in HNSCC and provides novel insights into immune checkpoint blockade treatment.
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Project description:Alterations in the epigenetic machinery in both tumor and immune cells contribute to bladder cancer (BC) development, constituting a promising target as an alternative therapeutic option. Here, we have explored the effects of a novel histone deacetylase (HDAC) inhibitor CM-1758, alone or in combination with immune checkpoint inhibitors (ICI) in BC. We determined the antitumor effects of CM-1758 in various BC cell lines together with the induction of broad transcriptional changes, with focus on the epigenetic regulation of PD-L1. Using an immunocompetent syngeneic mouse model of metastatic BC, we studied the effects of CM-1758 alone or in combination with anti-PD-L1 not only on tumor cells, but also in the tumor microenvironment. In vitro, we found that CM-1758 has cytotoxic and cytostatic effects either by inducing apoptosis or cell cycle arrest in BC cells at low micromolar levels. PD-L1 is epigenetically regulated by histone acetylation marks and is induced after treatment with CM-1758. We also observed that treatment with CM-1758 led to an important delay in tumor growth and a higher CD8+ T cell tumor infiltration. Moreover, anti-PD-L1 alone or in combination with CM-1758 reprogramed macrophage differentiation towards a M1-like polarization state and increased of pro-inflammatory cytokines systemically, yielding potential further cooperative antitumor effects. Our results suggest the possibility of combining HDAC inhibitors with immunotherapies for the management of advanced metastatic BC.
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Project description:Study hypothesis: We hypothesise that the reduced risk of colorectal cancer through increased fibre intake is mediated in part through changes in global protein acetylation.
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Project description:Histone H3 lysine 4 tri-methylation (H3K4me3) is a hallmark of transcription initiation, but how H3K4me3 is demethylated during gene repression is poorly understood. Jhd2, a JmjC domain protein, was recently identified as the major H3K4me3 histone demethylase (HDM) in S. cerevisiae. While JHD2 is required for removal of methylation upon gene repression, deletion of JHD2 does not result in increased levels of H3K4me3 in bulk histones, indicating that this HDM is unable to demethylate histones during steady state conditions. In this study, we showed that this was due to the negative regulation of Jhd2 activity by histone H3 lysine 14 acetylation, which co-localizes with H3K4me3 across the yeast genome. We demonstrated that loss of the histone H3-specific acetyltransferases (HATs) resulted in genome-wide-depletion of H3K4me3, and this was not due to a transcription defect. Moreover, H3K4me3 levels were reestablished in HAT mutants following loss of JHD2, which suggested that H3-specific HATs and Jhd2 served opposing functions in regulating H3K4me3 levels. We revealed the molecular basis for this suppression by demonstrating that histone H3K14 acetylation negatively regulated Jhd2 demethylase activity on an acetylated peptide in vitro. These results revealed the existence of a general mechanism for removal of H3K4me3 following gene repression. Examination of H3K4me3 in WT, ada2sas3, ada2sas3jhd2, and jhd2 strains.
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