TY - JOUR AU - Wang, Ya-Ting AU - Chen, Jocelyn AU - Chang, Chou-Wei AU - Jen, Jayu AU - Huang, Tzu-Yu AU - Chen, Chun-Ming AU - Shen, Roger AU - Liang, Suh-Yuen AU - Cheng, I-Cheng AU - Yang, Shuenn-Chen AU - Lai, Wu-Wei AU - Cheng, Kuang-Hung AU - Hsieh, Tao-Shih AU - Lai, Ming-Zong AU - Cheng, Hung-Chi AU - Wang, Yi-Ching AU - Chen, Ruey-Hwa T1 - Ubiquitination of tumor suppressor PML regulates prometastatic and immunosuppressive tumor microenvironment PY - 2017/08/01/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI89957 VL - 127 IS - 8 UR - https://doi.org/10.1172/JCI89957 SP - 2982 EP - 2997 PB - The American Society for Clinical Investigation ER -