DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells

Hiro Sato; Atsuko Niimi; Takaaki Yasuhara; Tiara Bunga Mayang Permata; Yoshihiko Hagiwara; Mayu Isono; Endang Nuryadi; Ryota Sekine; Takahiro Oike; Sangeeta Kakoti; Yuya Yoshimoto; Kathryn D. Held; Yoshiyuki Suzuki; Koji Kono; Kiyoshi Miyagawa; Takashi Nakano; Atsushi Shibata

doi:10.1038/s41467-017-01883-9

DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells

Hiro Sato, Atsuko Niimi, Takaaki Yasuhara, Tiara Bunga Mayang Permata, Yoshihiko Hagiwara, Mayu Isono, Endang Nuryadi, Ryota Sekine, Takahiro Oike, Sangeeta Kakoti, Yuya Yoshimoto, Kathryn D. Held, Yoshiyuki Suzuki, Koji Kono, Kiyoshi Miyagawa, Takashi Nakano, Atsushi Shibata

Research output: Contribution to journal › Article › peer-review

507 Citations (Scopus)

Abstract

Accumulating evidence suggests that exogenous cellular stress induces PD-L1 upregulation in cancer. A DNA double-strand break (DSB) is the most critical type of genotoxic stress, but the involvement of DSB repair in PD-L1 expression has not been investigated. Here we show that PD-L1 expression in cancer cells is upregulated in response to DSBs. This upregulation requires ATM/ATR/Chk1 kinases. Using an siRNA library targeting DSB repair genes, we discover that BRCA2 depletion enhances Chk1-dependent PD-L1 upregulation after X-rays or PARP inhibition. In addition, we show that Ku70/80 depletion substantially enhances PD-L1 upregulation after X-rays. The upregulation by Ku80 depletion requires Chk1 activation following DNA end-resection by Exonuclease 1. DSBs activate STAT1 and STAT3 signalling, and IRF1 is required for DSB-dependent PD-L1 upregulation. Thus, our findings reveal the involvement of DSB repair in PD-L1 expression and provide mechanistic insight into how PD-L1 expression is regulated after DSBs.

Original language	English
Article number	1751
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-01883-9
Publication status	Published - 01-12-2017
Externally published	Yes

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

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

Access to Document

10.1038/s41467-017-01883-9

Cite this

Sato, H., Niimi, A., Yasuhara, T., Permata, T. B. M., Hagiwara, Y., Isono, M., Nuryadi, E., Sekine, R., Oike, T., Kakoti, S., Yoshimoto, Y., Held, K. D., Suzuki, Y., Kono, K., Miyagawa, K., Nakano, T., & Shibata, A. (2017). DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells. Nature communications, 8(1), Article 1751. https://doi.org/10.1038/s41467-017-01883-9

@article{39b46904523141c483b200fbc9a495fb,

title = "DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells",

abstract = "Accumulating evidence suggests that exogenous cellular stress induces PD-L1 upregulation in cancer. A DNA double-strand break (DSB) is the most critical type of genotoxic stress, but the involvement of DSB repair in PD-L1 expression has not been investigated. Here we show that PD-L1 expression in cancer cells is upregulated in response to DSBs. This upregulation requires ATM/ATR/Chk1 kinases. Using an siRNA library targeting DSB repair genes, we discover that BRCA2 depletion enhances Chk1-dependent PD-L1 upregulation after X-rays or PARP inhibition. In addition, we show that Ku70/80 depletion substantially enhances PD-L1 upregulation after X-rays. The upregulation by Ku80 depletion requires Chk1 activation following DNA end-resection by Exonuclease 1. DSBs activate STAT1 and STAT3 signalling, and IRF1 is required for DSB-dependent PD-L1 upregulation. Thus, our findings reveal the involvement of DSB repair in PD-L1 expression and provide mechanistic insight into how PD-L1 expression is regulated after DSBs.",

author = "Hiro Sato and Atsuko Niimi and Takaaki Yasuhara and Permata, {Tiara Bunga Mayang} and Yoshihiko Hagiwara and Mayu Isono and Endang Nuryadi and Ryota Sekine and Takahiro Oike and Sangeeta Kakoti and Yuya Yoshimoto and Held, {Kathryn D.} and Yoshiyuki Suzuki and Koji Kono and Kiyoshi Miyagawa and Takashi Nakano and Atsushi Shibata",

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = dec,

day = "1",

doi = "10.1038/s41467-017-01883-9",

language = "English",

volume = "8",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells

AU - Sato, Hiro

AU - Niimi, Atsuko

AU - Yasuhara, Takaaki

AU - Permata, Tiara Bunga Mayang

AU - Hagiwara, Yoshihiko

AU - Isono, Mayu

AU - Nuryadi, Endang

AU - Sekine, Ryota

AU - Oike, Takahiro

AU - Kakoti, Sangeeta

AU - Yoshimoto, Yuya

AU - Held, Kathryn D.

AU - Suzuki, Yoshiyuki

AU - Kono, Koji

AU - Miyagawa, Kiyoshi

AU - Nakano, Takashi

AU - Shibata, Atsushi

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Accumulating evidence suggests that exogenous cellular stress induces PD-L1 upregulation in cancer. A DNA double-strand break (DSB) is the most critical type of genotoxic stress, but the involvement of DSB repair in PD-L1 expression has not been investigated. Here we show that PD-L1 expression in cancer cells is upregulated in response to DSBs. This upregulation requires ATM/ATR/Chk1 kinases. Using an siRNA library targeting DSB repair genes, we discover that BRCA2 depletion enhances Chk1-dependent PD-L1 upregulation after X-rays or PARP inhibition. In addition, we show that Ku70/80 depletion substantially enhances PD-L1 upregulation after X-rays. The upregulation by Ku80 depletion requires Chk1 activation following DNA end-resection by Exonuclease 1. DSBs activate STAT1 and STAT3 signalling, and IRF1 is required for DSB-dependent PD-L1 upregulation. Thus, our findings reveal the involvement of DSB repair in PD-L1 expression and provide mechanistic insight into how PD-L1 expression is regulated after DSBs.

AB - Accumulating evidence suggests that exogenous cellular stress induces PD-L1 upregulation in cancer. A DNA double-strand break (DSB) is the most critical type of genotoxic stress, but the involvement of DSB repair in PD-L1 expression has not been investigated. Here we show that PD-L1 expression in cancer cells is upregulated in response to DSBs. This upregulation requires ATM/ATR/Chk1 kinases. Using an siRNA library targeting DSB repair genes, we discover that BRCA2 depletion enhances Chk1-dependent PD-L1 upregulation after X-rays or PARP inhibition. In addition, we show that Ku70/80 depletion substantially enhances PD-L1 upregulation after X-rays. The upregulation by Ku80 depletion requires Chk1 activation following DNA end-resection by Exonuclease 1. DSBs activate STAT1 and STAT3 signalling, and IRF1 is required for DSB-dependent PD-L1 upregulation. Thus, our findings reveal the involvement of DSB repair in PD-L1 expression and provide mechanistic insight into how PD-L1 expression is regulated after DSBs.

UR - http://www.scopus.com/inward/record.url?scp=85035020009&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85035020009&partnerID=8YFLogxK

U2 - 10.1038/s41467-017-01883-9

DO - 10.1038/s41467-017-01883-9

M3 - Article

C2 - 29170499

AN - SCOPUS:85035020009

SN - 2041-1723

VL - 8

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 1751

ER -

DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells

Abstract

All Science Journal Classification (ASJC) codes

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this