Ubiquitination of tumor suppressor PML regulates prometastatic and immunosuppressive tumor microenvironment

Ya Ting Wang, Jocelyn Chen, Chou Wei Chang, Jayu Jen, Tzu Yu Huang, Chun Ming Chen, Roger Shen, Suh Yuen Liang, I. Cheng Cheng, Shuenn Chen Yang, Wu Wei Lai, Kuang Hung Cheng, Tao Shih Hsieh, Ming Zong Lai, Hung Chi Cheng, Yi Ching Wang, Ruey Hwa Chen

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2982-2997
Number of pages16
JournalJournal of Clinical Investigation
Volume127
Issue number8
DOIs
Publication statusPublished - 2017 Aug 1

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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