ERα is a negative regulator of PD-L1 gene transcription in breast cancer

Liu, Lu; Shen, Yinghui; Zhu, Xuguo; Lv, Ruitu; Li, Shuangqi; Zhang, Zijing; Shi, Yujiang Geno; Tan, Li

doi:10.1016/j.bbrc.2018.09.005

Cited by 37 publications

(30 citation statements)

References 18 publications

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“…RNA was extracted from the cells using TRIzol reagent (Thermo Fisher Scientific, Waltham, MA, USA) according to the manufacturer’s protocol. The protocol of RT-qPCR was described in our previous study [ 13 ]. Gene expression levels were normalized to GAPDH .…”

Section: Methodsmentioning

confidence: 99%

“…Many studies have revealed the transcriptional regulatory mechanisms of the PD-L1 gene, including the inflammatory cytokines, specific transcription factors, and so on [ 10 , 11 , 12 , 13 ]. In addition, the epigenetic modifiers also play an important role in regulating PD-L1 gene transcription, altering the chromatin accessibility for the transcription factors through DNA methylation or histone modifications [ 14 , 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

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TET2 Inhibits PD-L1 Gene Expression in Breast Cancer Cells through Histone Deacetylation

Shen

Liu

Wang

et al. 2021

Cancers

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Activation of PD-1/PD-L1 checkpoint is a critical step for the immune evasion of malignant tumors including breast cancer. However, the epigenetic mechanism underlying the aberrant expression of PD-L1 in breast cancer cells remains poorly understood. To investigate the role of TET2 in the regulation of PD-L1 gene expression, quantitative reverse transcription PCR (RT-qPCR), Western blotting, chromatin immunoprecipitation (ChIP) assay and MeDIP/hMeDIP-qPCR were performed on MCF7 and MDA-MB-231 human breast cancer cells. Here, we reported that TET2 depletion upregulated PD-L1 gene expression in MCF7 cells. Conversely, ectopic expression of TET2 inhibited PD-L1 gene expression in MDA-MB-231 cells. Mechanistically, TET2 protein recruits histone deacetylases (HDACs) to PD-L1 gene promoter and orchestrates a repressive chromatin structure to suppress PD-L1 gene transcription, which is likely independent of DNA demethylation. Consistently, treatment with HDAC inhibitors upregulated PD-L1 gene expression in wild-type (WT) but not TET2 KO MCF7 cells. Furthermore, analysis of the CCLE and TCGA data showed a negative correlation between TET2 and PD-L1 expression in breast cancer. Taken together, our results identify a new epigenetic regulatory mechanism of PD-L1 gene transcription, linking the catalytic activity-independent role of TET2 to the anti-tumor immunity in breast cancer.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TET2 Inhibits PD-L1 Gene Expression in Breast Cancer Cells through Histone Deacetylation

Shen

Liu

Wang

et al. 2021

Cancers

Self Cite

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“…In studies using breast cancer cell lines, ERα was shown to be a negative regulator of PD-L1 gene transcription as revealed by the mutually exclusive expression pattern of ERα and PD-L1 (53). Moreover, analysis of TCGA data derived from human breast cancer samples demonstrated that the average PD-L1 mRNA levels of ERα-positive tumors were significantly lower than those of ERα-negative tumors (53). Thus, immune response and ER signaling do not seem to be completely independent phenomenon.…”

Section: The Immune Systemmentioning

confidence: 99%

The Tumor Microenvironment as a Regulator of Endocrine Resistance in Breast Cancer

et al. 2019

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Estrogen receptor positive breast neoplasias represent over 70% of diagnosed breast cancers. Depending on the stage at which the tumor is detected, HER2 status and genomic risk, endocrine therapy is combined with either radio, chemo and/or targeted therapy. A growing amount of evidence supports the notion that components of the tumor microenvironment play specific roles in response to treatment and that strategies targeting these key interactions with tumor cells could pave the way to a new generation of therapies. In this review, we analyze the evidence suggesting different components of the tumor microenvironment play a role in hormone receptor positive breast cancer progression. In particular we focus on the immune system, carcinoma associated fibroblasts and the extracellular matrix. Further insight into the cross talk between these constituents of the microenvironment and the tumor cells may lead to therapies that eliminate disseminated metastatic cells early on, and thus reduce distant disease relapse which is the leading cause of death for patients who are diagnosed with this illness.

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“…Recently, it was found that the same regulators of cell survival possess control over the expression of ICs, namely AP-1 [54], MYC [55], and ER-α [56]. This thus shows that oncogenes elicit tumorigenesis through several hallmarks of cancers as opposed to only aberrant cell proliferation and survival.…”

Section: Known Putative Master Regulators Of Icsmentioning

confidence: 99%

“…This phenomenon is reflected in the negative regulation of PD-L1 by ER-α signaling in breast cancer. ER-α regulates gene transcription through the direct binding of the receptor to regulatory regions (enhancers or silencers) of target genes [56]. The relationship between ER-α and PD-L1 has been cemented in a study that revealed estrogen deprivation or ER-α depletion induced PD-L1 expression in ER+ breast cancer in vitro and in vivo [66].…”

Section: Known Putative Master Regulators Of Icsmentioning

confidence: 99%

Transcriptional Regulation of Cancer Immune Checkpoints: Emerging Strategies for Immunotherapy

et al. 2020

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The study of immune evasion has gained a well-deserved eminence in cancer research by successfully developing a new class of therapeutics, immune checkpoint inhibitors, such as pembrolizumab and nivolumab, anti-PD-1 antibodies. By aiming at the immune checkpoint blockade (ICB), these new therapeutics have advanced cancer treatment with notable increases in overall survival and tumor remission. However, recent reports reveal that 40–60% of patients fail to benefit from ICB therapy due to acquired resistance or tumor relapse. This resistance may stem from increased expression of co-inhibitory immune checkpoints or alterations in the tumor microenvironment that promotes immune suppression. Because these mechanisms are poorly elucidated, the transcription factors that regulate immune checkpoints, known as “master regulators”, have garnered interest. These include AP-1, IRF-1, MYC, and STAT3, which are known to regulate PD/PD-L1 and CTLA-4. Identifying these and other potential master regulators as putative therapeutic targets or biomarkers can be facilitated by mining cancer literature, public datasets, and cancer genomics resources. In this review, we describe recent advances in master regulator identification and characterization of the mechanisms underlying immune checkpoints regulation, and discuss how these master regulators of immune checkpoint molecular expression can be targeted as a form of auxiliary therapeutic strategy to complement traditional immunotherapy.

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ERα is a negative regulator of PD-L1 gene transcription in breast cancer

Cited by 37 publications

References 18 publications

TET2 Inhibits PD-L1 Gene Expression in Breast Cancer Cells through Histone Deacetylation

TET2 Inhibits PD-L1 Gene Expression in Breast Cancer Cells through Histone Deacetylation

The Tumor Microenvironment as a Regulator of Endocrine Resistance in Breast Cancer

Transcriptional Regulation of Cancer Immune Checkpoints: Emerging Strategies for Immunotherapy

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