Hippo effector YAP directly regulates the expression of PD-L1 transcripts in EGFR-TKI-resistant lung adenocarcinoma

Lee, Byung-Soo; Park, Dong Il; Lee, Da Hye; Lee, Jeong Eun; Yeo, Min‐Kyung; Park, Yeon Hee; Lim, Dae Sik; Choi, Wonyoung; Yoo, Geon; Kim, Han-byul; Kang, Dahyun; Moon, Jae Young; Jung, Sung Soo; Kim, Ju Ock; Cho, Sang Yeon; Park, Hee Sun; Chung, Chaeuk

doi:10.1016/j.bbrc.2017.07.007

Cited by 138 publications

(149 citation statements)

References 24 publications

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“…Indeed, the expression of miR-130a mimic or miR-130a sponge suppressed or enhanced VGLL4 and PD-L1 levels, respectively, in A549 cells (Fig 6A-C). Consistent with previous reports Lee et al, 2017;Miao et al, 2017;Janse van Rensburg et al, 2018;Kim et al, 2018), we observed an increased PD-L1 mRNA level when YAP5SA, a transcriptionally active and Hippo pathway-resistant YAP mutant, was expressed in A549 cells (Fig EV5B). Consistent with previous reports Lee et al, 2017;Miao et al, 2017;Janse van Rensburg et al, 2018;Kim et al, 2018), we observed an increased PD-L1 mRNA level when YAP5SA, a transcriptionally active and Hippo pathway-resistant YAP mutant, was expressed in A549 cells (Fig EV5B).…”

Section: Yap Inhibits Ifnc-inducible Pd-l1 Expressionsupporting

confidence: 92%

“…Furthermore, expression of YAP target genes CTGF and CYR61 was slightly decreased by inhibition of miR-130a ( Fig 6D), while knockdown of VGLL4 slightly increased miR-130a expression ( Fig EV5A), confirming the positive feedback loop of YAP-miR-130a-VGLL4 axis. Consistent with previous reports Lee et al, 2017;Miao et al, 2017;Janse van Rensburg et al, 2018;Kim et al, 2018), we observed an increased PD-L1 mRNA level when YAP5SA, a transcriptionally active and Hippo pathway-resistant YAP mutant, was expressed in A549 cells ( Fig EV5B). However, we detected a strong inhibition on ◀ Figure 3.…”

Section: Yap Inhibits Ifnc-inducible Pd-l1 Expressionsupporting

confidence: 92%

“…Recently, several studies suggest that YAP/TAZ promote PD-L1 expression through TEAD-mediated transcriptional regulation Lee et al, 2017;Miao et al, 2017;Janse van Rensburg et al, 2018;Kim et al, 2018). Interestingly, one study showed that VGLL4 expression is repressed by YAP/TEAD transcriptional complex through miR-130a , which promotes us to test whether miR-130a and YAP could suppress IFNc-inducible PD-L1 expression.…”

Section: Yap Inhibits Ifnc-inducible Pd-l1 Expressionmentioning

confidence: 99%

“…Many studies reported that the dysregulation of several oncogenic or tumor-suppressive pathways constitutively activates the expression of PD-L1, suggesting that this is a general mechanism of tumorigenesis. PTEN deletions, PI3K/AKT mutations (Parsa et al, 2007;Lastwika et al, 2016), EGFR mutations (Akbay et al, 2013), MYC overexpression (Casey et al, 2016), CDK5 disruption (Dorand et al, 2016), and YAP/TAZ activation Lee et al, 2017;Miao et al, 2017;Janse van Rensburg et al, 2018;Kim et al, 2018) represent a rapidly growing list of genetic mechanisms of constitutive PD-L1 expression. Expression of PD-L1 can be induced by many cytokines, of which interferon-gamma (IFNc) is the most potent via JAK1/2-STAT1/2/3-IRF1 signaling axis, with IRF1 binding to PD-L1 promoter (Dong et al, 2002;Loke & Allison, 2003;Lee et al, 2006;Garcia-Diaz et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Loss of VGLL 4 suppresses tumor PD ‐L1 expression and immune evasion

Deng

et al. 2018

The EMBO Journal

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Targeting immune checkpoints, such as PD‐L1 and its receptor PD‐1, has opened a new avenue for treating cancers. Understanding the regulatory mechanism of PD‐L1 and PD‐1 will improve the clinical response rate and efficacy of PD‐1/PD‐L1 blockade in cancer patients and the development of combinatorial strategies. VGLL4 inhibits YAP‐induced cell proliferation and tumorigenesis through competition with YAP for binding to TEADs. However, whether VGLL4 has a role in anti‐tumor immunity is largely unknown. Here, we found that disruption of Vgll4 results in potent T cell‐mediated tumor regression in murine syngeneic models. VGLL4 deficiency reduces PD‐L1 expression in tumor cells. VGLL4 interacts with IRF2BP2 and promotes its protein stability through inhibiting proteasome‐mediated protein degradation. Loss of IRF2BP2 results in persistent binding of IRF2, a transcriptional repressor, to PD‐L1 promoter. In addition, YAP inhibits IFNγ‐inducible PD‐L1 expression partially through suppressing the expression of VGLL4 and IRF1 by YAP target gene miR‐130a. Our study identifies VGLL4 as an important regulator of PD‐L1 expression and highlights a central role of VGLL4 and YAP in the regulation of tumor immunity.

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Section: Yap Inhibits Ifnc-inducible Pd-l1 Expressionsupporting

confidence: 92%

Section: Yap Inhibits Ifnc-inducible Pd-l1 Expressionsupporting

confidence: 92%

Section: Yap Inhibits Ifnc-inducible Pd-l1 Expressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Loss of VGLL 4 suppresses tumor PD ‐L1 expression and immune evasion

Deng

et al. 2018

The EMBO Journal

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“…103 Most recent studies demonstrated the positive correlation of YAP1 and PD-L1 expressions in NSCLC patients. 41,104 In addition, these studies have shown that YAP1 directly upregulates PD-L1 transcription.…”

Section: Programmed Cell Death Ligand 1 (Pd-l1)mentioning

confidence: 95%

A time for YAP1: Tumorigenesis, immunosuppression and targeted therapy

Shibata

Ham

Hoque

2018

Intl Journal of Cancer

138

143

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YAP1 is one of the most important effectors of the Hippo pathway and has crosstalk with other cancer promoting pathways. YAP1 contributes to cancer development in various ways that include promoting malignant phenotypes, expansion of cancer stem cells and drug resistance of cancer cells. Because pharmacologic or genetic inhibition of YAP1 suppresses tumor progression and increases the drug sensitivity, targeting YAP1 may open a fertile avenue for a novel therapeutic approach in relevant cancers. Recent enormous studies have established the efficacy of immunotherapy, and several immune checkpoint blockades are in clinical use or in the phase of development to treat various cancer types. Immunosuppression in the tumor microenvironment (TME) induced by cancer cells, immune cells and associated stromal cells promotes tumor progression and causes drug resistance. Accumulated evidences of scientific efforts from the last few years suggest that YAP1 influences macrophages, myeloid-derived suppressor cells and regulatory T-cells to facilitate immunosuppressive TME. Although the underlying mechanisms is not clearly discerned, it is evident that YAP1 activating pathways in different cellular components induce immunosuppressive TME. In this review, we summarize the evidences involved in the dual roles of YAP1 in cancer development and immunosuppression in the TME. We also discuss the possibility of YAP1 as a novel therapeutic target.

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TAZ facilitates breast tumor growth by promoting an immune‐suppressive tumor microenvironment

Gershoni,

Hassin,

Nataraj

et al. 2023

Molecular Oncology

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The core Hippo pathway module consists of a tumor‐suppressive kinase cascade that inhibits the transcriptional coactivators Yes‐associated protein (YAP) and WW domain‐containing transcription regulator protein 1 (WWTR1; also known as TAZ). When the Hippo pathway is downregulated, as often occurs in breast cancer, YAP/TAZ activity is induced. To elaborate the roles of TAZ in triple‐negative breast cancer (TNBC), we depleted Taz in murine TNBC 4T1 cells, using either CRISPR/Cas9 or small hairpin RNA (shRNA). TAZ‐depleted cells and their controls, harboring wild‐type levels of TAZ, were orthotopically injected into the mammary fat pads of syngeneic BALB/c female mice, and mice were monitored for tumor growth. TAZ depletion resulted in smaller tumors compared to the tumors generated by control cells, in line with the notion that TAZ functions as an oncogene in breast cancer. Tumors, as well as their corresponding in vitro cultured cells, were then subjected to gene expression profiling by RNA sequencing (RNA‐seq). Interestingly, pathway analysis of the RNA‐seq data indicated a TAZ‐dependent enrichment of ‘Inflammatory Response', a pathway correlated with TAZ expression levels also in human breast cancer tumors. Specifically, the RNA‐seq analysis predicted a significant depletion of regulatory T cells (Tregs) in TAZ‐deficient tumors, which was experimentally validated by the staining of tumor sections and by quantitative cytometry by time of flight (CyTOF). Strikingly, the differences in tumor size were completely abolished in immune‐deficient mice, demonstrating that the immune‐modulatory capacity of TAZ is critical for its oncogenic activity in this setting. Cytokine array analysis of conditioned medium from cultured cells revealed that TAZ increased the abundance of a small group of cytokines, including plasminogen activator inhibitor 1 (Serpin E1; also known as PAI‐1), CCN family member 4 (CCN4; also known as WISP‐1) and interleukin‐23 (IL‐23), suggesting a potential mechanistic explanation for its in vivo immunomodulatory effect. Together, our results imply that TAZ functions in a non‐cell‐autonomous manner to modify the tumor immune microenvironment and dampen the anti‐tumor immune response, thereby facilitating tumor growth.

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Hippo effector YAP directly regulates the expression of PD-L1 transcripts in EGFR-TKI-resistant lung adenocarcinoma

Cited by 138 publications

References 24 publications

Loss of VGLL 4 suppresses tumor PD ‐L1 expression and immune evasion

Loss of VGLL 4 suppresses tumor PD ‐L1 expression and immune evasion

A time for YAP1: Tumorigenesis, immunosuppression and targeted therapy

TAZ facilitates breast tumor growth by promoting an immune‐suppressive tumor microenvironment

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