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 language | English (US) |
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Pages (from-to) | 840-855.e8 |
Journal | Cancer cell |
Volume | 32 |
Issue number | 6 |
DOIs | |
State | Published - Dec 11 2017 |
Funding
We thank Drs. C. Brennan, A. Sanz-Clemente, C. He, W. Zhang, and S. Huang for providing reagents and advice. This work was supported by US NIH grants NS093843 , NS095634 , CA158911 (S.Y.C.); a Brain Cancer Research Award from James S. McDonnell Foundation (B.H.); L32 MD010147 and T32 CA070085 (A.A.A.), CA163205 , CA175875 , NS083767 (I.N.), CA159467 , NS080619 (C.D.J.), NS081774 (J.A.K.), LM012011 (X.L.), LM011673 (S.L.), NS102669 (C.H.), AA021751 (X.-M.Y.), and The Lou and Jean Malnati Brain Tumor Institute at Northwestern Medcine (S.-Y.C., B.H.). S.-Y.C. is a Zell Scholar at Northwestern University.
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
- Cancer Research