Author:
Tamai Keiichi,Nakamura-Shima Mao,Shibuya-Takahashi Rie,Kanno Shin-Ichiro,Yasui Akira,Mochizuki Mai,Iwai Wataru,Wakui Yuta,Abue Makoto,Yamamoto Kuniharu,Miura Koh,Mizuma Masamichi,Unno Michiaki,Kawamura Sadafumi,Sato Ikuro,Yasuda Jun,Yamaguchi Kazunori,Sugamura Kazuo,Satoh Kennichi
Abstract
AbstractCancer 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.
Funder
Japan Agency for Medical Research and Development
Japan Society for the Promotion of Science
Publisher
Springer Science and Business Media LLC
Cited by
16 articles.
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