TY - JOUR
T1 - BEX2 suppresses mitochondrial activity and is required for dormant cancer stem cell maintenance in intrahepatic cholangiocarcinoma
AU - Tamai, Keiichi
AU - Nakamura-Shima, Mao
AU - Shibuya-Takahashi, Rie
AU - Kanno, Shin Ichiro
AU - Yasui, Akira
AU - Mochizuki, Mai
AU - Iwai, Wataru
AU - Wakui, Yuta
AU - Abue, Makoto
AU - Yamamoto, Kuniharu
AU - Miura, Koh
AU - Mizuma, Masamichi
AU - Unno, Michiaki
AU - Kawamura, Sadafumi
AU - Sato, Ikuro
AU - Yasuda, Jun
AU - Yamaguchi, Kazunori
AU - Sugamura, Kazuo
AU - Satoh, Kennichi
N1 - Funding Information:
This research was supported in part by the Biomedical Research Core of Tohoku University Graduate School of Medicine. This research was supported in part by JSPS KAKENHI grant numbers JP: 19K08430, 17K10716, and 16K07132, and Practical Research for Innovative Cancer Control from AMED by grant number JP17ck0106197, The Cooperative Research Project Program of Joint Usage/Research Center at The Institute of Development, Aging and Cancer, Tohoku University, and Takeda Medical Foundation.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12
Y1 - 2020/12
N2 - Cancer stem cells (CSCs) define a subpopulation of cancer cells that are resistant to therapy. However, little is known of how CSC characteristics are regulated. We previously showed that dormant cancer stem cells are enriched with a CD274low fraction of cholangiocarcinoma cells. Here we found that BEX2 was highly expressed in CD274low cells, and that BEX2 knockdown decreased the tumorigenicity and G0 phase of cholangiocarcinoma cells. BEX2 was found to be expressed predominantly in G0 phase and starvation induced the USF2 transcriptional factor, which induced BEX2 transcription. Comprehensive screening of BEX2 binding proteins identified E3 ubiquitin ligase complex proteins, FEM1B and CUL2, and a mitochondrial protein TUFM, and further demonstrated that knockdown of BEX2 or TUFM increased mitochondria-related oxygen consumption and decreased tumorigenicity in cholangiocarcinoma cells. These results suggest that BEX2 is essential for maintaining dormant cancer stem cells through the suppression of mitochondrial activity in cholangiocarcinoma.
AB - Cancer stem cells (CSCs) define a subpopulation of cancer cells that are resistant to therapy. However, little is known of how CSC characteristics are regulated. We previously showed that dormant cancer stem cells are enriched with a CD274low fraction of cholangiocarcinoma cells. Here we found that BEX2 was highly expressed in CD274low cells, and that BEX2 knockdown decreased the tumorigenicity and G0 phase of cholangiocarcinoma cells. BEX2 was found to be expressed predominantly in G0 phase and starvation induced the USF2 transcriptional factor, which induced BEX2 transcription. Comprehensive screening of BEX2 binding proteins identified E3 ubiquitin ligase complex proteins, FEM1B and CUL2, and a mitochondrial protein TUFM, and further demonstrated that knockdown of BEX2 or TUFM increased mitochondria-related oxygen consumption and decreased tumorigenicity in cholangiocarcinoma cells. These results suggest that BEX2 is essential for maintaining dormant cancer stem cells through the suppression of mitochondrial activity in cholangiocarcinoma.
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U2 - 10.1038/s41598-020-78539-0
DO - 10.1038/s41598-020-78539-0
M3 - Article
C2 - 33299012
AN - SCOPUS:85097405905
SN - 2045-2322
VL - 10
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 21592
ER -
