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Ubiquitination of tumor suppressor PML regulates prometastatic and immunosuppressive tumor microenvironment.

ABSTRACT: The tumor microenvironment plays an important role in tumor growth and metastasis. However, the mechanism by which tumor cells regulate the cell and non-cell constituents of surrounding stroma remains incompletely understood. Promyelocytic leukemia (PML) is a pleiotropic tumor suppressor, but its role in tumor microenvironment regulation is poorly characterized. PML is frequently downregulated in many cancer types, including lung cancer. Here, we identify a PML ubiquitination pathway that is mediated by WD repeat 4-containing cullin-RING ubiquitin ligase 4 (CRL4WDR4). Clinically, this PML degradation pathway is hyperactivated in lung cancer and correlates with poor prognosis. The WDR4/PML axis induces a set of cell-surface or secreted factors, including CD73, urokinase-type plasminogen activator receptor (uPAR), and serum amyloid A2 (SAA2), which elicit paracrine effects to stimulate migration, invasion, and metastasis in multiple lung cancer models. In xenograft and genetically engineered mouse models, the WDR4/PML axis elevates intratumoral Tregs and M2-like macrophages and reduces CD8+ T cells to promote lung tumor growth. These immunosuppressive effects were all reversed by CD73 blockade. Our study identifies WDR4 as an oncoprotein that negatively regulates PML via ubiquitination to promote lung cancer progression by fostering an immunosuppressive and prometastatic tumor microenvironment, suggesting the potential of immune-modulatory approaches for treating lung cancer with aberrant PML degradation.

SUBMITTER: Wang YT

PROVIDER: S-EPMC5531412 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Ubiquitination of tumor suppressor PML regulates prometastatic and immunosuppressive tumor microenvironment.

Wang Ya-Ting YT Chen Jocelyn J Chang Chou-Wei CW Jen Jayu J Huang Tzu-Yu TY Chen Chun-Ming CM Shen Roger R Liang Suh-Yuen SY Cheng I-Cheng IC Yang Shuenn-Chen SC Lai Wu-Wei WW Cheng Kuang-Hung KH Hsieh Tao-Shih TS Lai Ming-Zong MZ Cheng Hung-Chi HC Wang Yi-Ching YC Chen Ruey-Hwa RH

The Journal of clinical investigation 20170710 8

The tumor microenvironment plays an important role in tumor growth and metastasis. However, the mechanism by which tumor cells regulate the cell and non-cell constituents of surrounding stroma remains incompletely understood. Promyelocytic leukemia (PML) is a pleiotropic tumor suppressor, but its role in tumor microenvironment regulation is poorly characterized. PML is frequently downregulated in many cancer types, including lung cancer. Here, we identify a PML ubiquitination pathway that is med ...[more]

PMID: 28691927

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Dataset Information

Ubiquitination of tumor suppressor PML regulates prometastatic and immunosuppressive tumor microenvironment.

Publications

Ubiquitination of tumor suppressor PML regulates prometastatic and immunosuppressive tumor microenvironment.

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