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
N1 - Funding Information:
We thank Yoshimi Omi, Akiko Shibata, Yuka Hirota, Yuka Kimura, Yoko Hayashi, Shiho Nakanishi and Mika Sato for assisting with the lab work and all the supports. We also thank S. Tomogane, S. Sato, Y. Komatsu, M. Saito, A. Sakurai and Y. Yoshimatsu for their support regarding the initial findings of IR or chemotherapeutic-agent-dependent PD-L1 upregulation. Dr. Hiro Sato appreciates Drs. T. Ohno, J.I. Saitoh, H. Kawamura, N. Kubo, T. Mizukami, A. Adachi, M. Iwanaga, S. Shiba, M. Onishi and Y. Mori for their support in the hospital work during the revision work. This work was supported by JSPS KAKENHI Grant Numbers JP26701005 and JP17H04713 to A.S., JP16H05388 to T.N., JP17K16420 and JP15K19771 to H.S., the Cell Science Research Foundation, the Daiichi Sankyo Foundation of Life Science and the Takeda Science Foundation. This work was supported by the Program of the network-type Joint Usage/Research Center for Radiation Disaster Medical Science of Hiroshima University, Nagasaki University and Fukushima Medical University. This work was also supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan for programs for Leading Graduate Schools, Cultivating Global Leaders in Heavy Ion Therapeutics and Engineering.
Publisher Copyright:
© 2017 The Author(s).
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
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 -
