MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma

• Published in: Cancer cell Vol. 32; no. 6; pp. 840 - 855.e8
• Main Authors: Huang, Tianzhi, Kim, Chung Kwon, Alvarez, Angel A., Pangeni, Rajendra P., Wan, Xuechao, Song, Xiao, Shi, Taiping, Yang, Yongyong, Sastry, Namratha, Horbinski, Craig M., Lu, Songjian, Stupp, Roger, Kessler, John A., Nishikawa, Ryo, Nakano, Ichiro, Sulman, Erik P., Lu, Xinghua, James, Charles David, Yin, Xiao-Ming, Hu, Bo, Cheng, Shi-Yuan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.12.2017; Cell Press
• Subjects: Animals; ATG4B; ATG4B inhibitor NSC185058; autophagy; Autophagy - physiology; Autophagy-Related Proteins - metabolism; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Carcinogenesis - metabolism; Cell Line, Tumor; combination therapy; Cysteine Endopeptidases - metabolism; glioblastoma; Glioblastoma - metabolism; Glioblastoma - pathology; glioma stem-like cells; Humans; Mice; Mice, Nude; MST4/STK26; Phosphorylation; Protein-Serine-Threonine Kinases - metabolism; Radiation Tolerance; tumor response to radiation; tumorigenicity; Xenograft Model Antitumor Assays; ATG4B inhibitor NSC185058; glioblastoma; autophagy; tumorigenicity; tumor response to radiation; glioma stem-like cells; ATG4B; combination therapy; phosphorylation; MST4/STK26
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2017.11.005

ATG4B stimulates autophagy by promoting autophagosome formation through reversible modification of ATG8. We identify ATG4B as a substrate of mammalian sterile20-like kinase (STK) 26/MST4. MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux. Inhibition of MST4 or ATG4B activities using genetic approaches or an inhibitor of ATG4B suppresses autophagy and the tumorigenicity of glioblastoma (GBM) cells. Furthermore, radiation induces MST4 expression, ATG4B phosphorylation, and autophagy. Inhibiting ATG4B in combination with radiotherapy in treating mice with intracranial GBM xenograft markedly slows tumor growth and provides a significant survival benefit. Our work describes an MST4-ATG4B signaling axis that influences GBM autophagy and malignancy, and whose therapeutic targeting enhances the anti-tumor effects of radiotherapy. [Display omitted] •MST4 kinase regulates the growth, sphere formation, and tumorigenicity of GBM cells•MST4 stimulates autophagy by activating ATG4B through phosphorylation of ATG4B S383•Radiation increases MST4 expression and ATG4B phosphorylation, inducing autophagy•Inhibiting ATG4B enhances the anti-tumor effects of radiotherapy in GBM PDX models Huang et al. show that radiation induces MST4 expression and that MST4 phosphorylates ATG4B at serine 383, which increases ATG4B activity and autophagic flux. Inhibition of ATG4B reduces autophagy and tumorigenicity of glioblastoma (GBM) cells and improves the impact of radiotherapy on GBM growth in mice.