Journal
CANCER CELL
Volume 32, Issue 6, Pages 840-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2017.11.005
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Funding
- US NIH [NS093843, NS095634, CA158911]
- Brain Cancer Research Award from James S. McDonnell Foundation [L32 MD010147, T32 CA070085, CA163205, CA175875, NS083767, NS080619, NS081774, LM012011, LM011673, NS102669, AA021751]
- The Lou and Jean Malnati Brain Tumor Institute at Northwestern Medcine
- Northwestern University
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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.
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