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 Hu*Shi Yuan Cheng

*Corresponding author for this work

Research output: Contribution to journalArticle

35 Citations (Scopus)

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

Fingerprint

Autophagy
Glioblastoma
Phosphorylation
Radiotherapy
Serine
Radiation
Neoplasms
Growth
Heterografts
Phosphotransferases

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

Cite this

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. / MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma. In: Cancer Cell. 2017 ; Vol. 32, No. 6. pp. 840-855.e8.
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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.",
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author = "Tianzhi Huang and Kim, {Chung Kwon} and Alvarez, {Angel A.} and Pangeni, {Rajendra P.} and Xuechao Wan and Xiao Song and Taiping Shi and Yongyong Yang and Namratha Sastry and Horbinski, {Craig M.} and Songjian Lu and Roger Stupp and Kessler, {John A.} and Ryo Nishikawa and Ichiro Nakano and Sulman, {Erik P.} and Xinghua Lu and James, {Charles David} and Yin, {Xiao Ming} and Bo Hu and Cheng, {Shi Yuan}",
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Huang, T, Kim, CK, Alvarez, AA, Pangeni, RP, Wan, X, Song, X, Shi, T, Yang, Y, Sastry, N, Horbinski, CM, Lu, S, Stupp, R, Kessler, JA, Nishikawa, R, Nakano, I, Sulman, EP, Lu, X, James, CD, Yin, XM, Hu, B & Cheng, SY 2017, 'MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma', Cancer Cell, vol. 32, no. 6, pp. 840-855.e8. https://doi.org/10.1016/j.ccell.2017.11.005

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

In: Cancer Cell, Vol. 32, No. 6, 11.12.2017, p. 840-855.e8.

Research output: Contribution to journalArticle

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T1 - MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma

AU - Huang, Tianzhi

AU - Kim, Chung Kwon

AU - Alvarez, Angel A.

AU - Pangeni, Rajendra P.

AU - Wan, Xuechao

AU - Song, Xiao

AU - Shi, Taiping

AU - Yang, Yongyong

AU - Sastry, Namratha

AU - Horbinski, Craig M.

AU - Lu, Songjian

AU - Stupp, Roger

AU - Kessler, John A.

AU - Nishikawa, Ryo

AU - Nakano, Ichiro

AU - Sulman, Erik P.

AU - Lu, Xinghua

AU - James, Charles David

AU - Yin, Xiao Ming

AU - Hu, Bo

AU - Cheng, Shi Yuan

PY - 2017/12/11

Y1 - 2017/12/11

N2 - 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.

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KW - ATG4B

KW - ATG4B inhibitor NSC185058

KW - MST4/STK26

KW - autophagy

KW - combination therapy

KW - glioblastoma

KW - glioma stem-like cells

KW - phosphorylation

KW - tumor response to radiation

KW - tumorigenicity

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