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

Tianzhi Huang, Chung Kwon Kim, Angel A. Alvarez, Rajendra P. Pangeni, Xuechao Wan, Xiao Song, Taiping Shi, Yongyong Yang, Namratha Sastry, Craig M. Horbinski, Songjian Lu, Roger Stupp, John A. Kessler, Ryo Nishikawa, Ichiro Nakano, Erik P. Sulman, Xinghua Lu, Charles David James, Xiao Ming Yin, Bo HuShi Yuan Cheng

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

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. 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.

Original languageEnglish (US)
Pages (from-to)840-855.e8
JournalCancer Cell
Volume32
Issue number6
DOIs
StatePublished - Dec 11 2017

Keywords

  • ATG4B
  • ATG4B inhibitor NSC185058
  • MST4/STK26
  • autophagy
  • combination therapy
  • glioblastoma
  • glioma stem-like cells
  • phosphorylation
  • tumor response to radiation
  • tumorigenicity

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Huang, T., Kim, C. K., Alvarez, A. A., Pangeni, R. P., Wan, X., Song, X., Shi, T., Yang, Y., Sastry, N., Horbinski, C. M., Lu, S., Stupp, R., Kessler, J. A., Nishikawa, R., Nakano, I., Sulman, E. P., Lu, X., James, C. D., Yin, X. M., ... Cheng, S. Y. (2017). MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma. Cancer Cell, 32(6), 840-855.e8. https://doi.org/10.1016/j.ccell.2017.11.005