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

doi:10.1016/j.ccell.2017.11.005

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 journal › Article › peer-review

190 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 language	English (US)
Pages (from-to)	840-855.e8
Journal	Cancer cell
Volume	32
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2017.11.005
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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ccell.2017.11.005

Cite this

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

@article{9fe8c1b9a139480ea2c7744fc7cd42f4,

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

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.",

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

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}",

note = "Publisher Copyright: {\textcopyright} 2017 The Authors",

year = "2017",

month = dec,

day = "11",

doi = "10.1016/j.ccell.2017.11.005",

language = "English (US)",

volume = "32",

pages = "840--855.e8",

journal = "Cancer cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "6",

}

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

TY - JOUR

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.

AB - 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.

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

UR - http://www.scopus.com/inward/record.url?scp=85038641667&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85038641667&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2017.11.005

DO - 10.1016/j.ccell.2017.11.005

M3 - Article

C2 - 29232556

AN - SCOPUS:85038641667

SN - 1535-6108

VL - 32

SP - 840-855.e8

JO - Cancer cell

JF - Cancer cell

IS - 6

ER -

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this