Enhanced histone H3 acetylation of the PD-L1 promoter via the COP1/c-Jun/HDAC3 axis is required for PD-L1 expression in drug-resistant cancer cells

Wang, Haifang; Fu, Chen; Du, Jie; Wang, Hongsheng; He, Rui; Yin, Xiaofeng; Li, Haixia; Li, Xin; Wang, Hongxia; Li, Kui; Liu, Zongcai; Qiu, Yurong

doi:10.1186/s13046-020-1536-x

Cited by 55 publications

(51 citation statements)

References 45 publications

(61 reference statements)

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“…Histone acetylation is an epigenetic modification enhancing gene transcription [ 38 ]. In some drug-resistant cancer cells, hyperactivated JNK/c-Jun signaling suppressed the histone deacetylase 3 (HADC3) expression, thereby elevating the histone H3 acetylation of the CD274 promoter [ 39 ]. The HADC inhibitor had a synergistic effect with α-PD-1 in the B16F10 tumor model [ 40 ].…”

Section: Epigenetic Regulationsmentioning

confidence: 99%

Regulation of PD-L1 expression in the tumor microenvironment

et al. 2021

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Programmed death-ligand 1 (PD-L1) on cancer cells engages with programmed cell death-1 (PD-1) on immune cells, contributing to cancer immune escape. For multiple cancer types, the PD-1/PD-L1 axis is the major speed-limiting step of the anti-cancer immune response. In this context, blocking PD-1/PD-L1 could restore T cells from exhausted status and eradicate cancer cells. However, only a subset of PD-L1 positive patients benefits from α-PD-1/PD-L1 therapies. Actually, PD-L1 expression is regulated by various factors, leading to the diverse significances of PD-L1 positivity. Understanding the mechanisms of PD-L1 regulation is helpful to select patients and enhance the treatment effect. In this review, we focused on PD-L1 regulators at the levels of transcription, post-transcription, post-translation. Besides, we discussed the potential applications of these laboratory findings in the clinic.

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Section: Epigenetic Regulationsmentioning

confidence: 99%

Regulation of PD-L1 expression in the tumor microenvironment

et al. 2021

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“…Other epigenetic targeting agents such as histone deacetylase inhibitors (HDACi) are also well established as candidate agents with the capacity to induce PD-L1 in cancer cells [ 161 – 164 ]. However, in MPM cell lines HDACi by themselves had modest effects on PD-L1, but when combined with decitabine, higher induction of this checkpoint inhibitor were observed [ 165 ].…”

Section: Outstanding Issues and Other Therapeutic Considerationsmentioning

confidence: 99%

Emerging avenues in immunotherapy for the management of malignant pleural mesothelioma

Gray

2021

BMC Pulm Med

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Background The role of immunotherapy in cancer is now well-established, and therapeutic options such as checkpoint inhibitors are increasingly being approved in many cancers such as non-small cell lung cancer (NSCLC). Malignant pleural mesothelioma (MPM) is a rare orphan disease associated with prior exposure to asbestos, with a dismal prognosis. Evidence from clinical trials of checkpoint inhibitors in this rare disease, suggest that such therapies may play a role as a treatment option for a proportion of patients with this cancer. Main text While the majority of studies currently focus on the established checkpoint inhibitors (CTLA4 and PD1/PDL1), there are many other potential checkpoints that could also be targeted. In this review I provide a synopsis of current clinical trials of immunotherapies in MPM, explore potential candidate new avenues that may become future targets for immunotherapy and discuss aspects of immunotherapy that may affect the clinical outcomes of such therapies in this cancer. Conclusions The current situation regarding checkpoint inhibitors in the management of MPM whilst encouraging, despite impressive durable responses, immune checkpoint inhibitors do not provide a long-term benefit to the majority of patients with cancer. Additional studies are therefore required to further delineate and improve our understanding of both checkpoint inhibitors and the immune system in MPM. Moreover, many new potential checkpoints have yet to be studied for their therapeutic potential in MPM. All these plus the existing checkpoint inhibitors will require the development of new biomarkers for patient stratification, response and also for predicting or monitoring the emergence of resistance to these agents in MPM patients. Other potential therapeutic avenues such CAR-T therapy or treatments like oncolytic viruses or agents that target the interferon pathway designed to recruit more immune cells to the tumor also hold great promise in this hard to treat cancer.

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“…In support of these observations, our results suggested that PKM2-mediated histone H3-Thr 11 phosphorylation participated in EGF-induced PD-L1 transcriptional expression. Interestingly, several studies suggested that histone H3 acetylation also play a key role in the regulation of PD-L1 gene expression in cancer cells (Lei et al, 2015;Wang et al, 2020). Given that the process of H3 phosphorylation usually recruits a histone modifying enzyme that would in turn generate the second modification (Cheung et al, 2000;Yang et al, 2012a), we supposed histone H3 acetylation may be also involved in EGFinduced PD-L1 expression in HCC cells.…”

Section: Discussionmentioning

confidence: 92%

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

et al. 2020

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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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Enhanced histone H3 acetylation of the PD-L1 promoter via the COP1/c-Jun/HDAC3 axis is required for PD-L1 expression in drug-resistant cancer cells

Cited by 55 publications

References 45 publications

Regulation of PD-L1 expression in the tumor microenvironment

Regulation of PD-L1 expression in the tumor microenvironment

Emerging avenues in immunotherapy for the management of malignant pleural mesothelioma

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

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