BEX2 suppresses mitochondrial activity and is required for dormant cancer stem cell maintenance in intrahepatic cholangiocarcinoma

Abstract 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 fo...

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Autores principales:	Keiichi Tamai, Mao Nakamura-Shima, Rie Shibuya-Takahashi, Shin-Ichiro Kanno, Akira Yasui, Mai Mochizuki, Wataru Iwai, Yuta Wakui, Makoto Abue, Kuniharu Yamamoto, Koh Miura, Masamichi Mizuma, Michiaki Unno, Sadafumi Kawamura, Ikuro Sato, Jun Yasuda, Kazunori Yamaguchi, Kazuo Sugamura, Kennichi Satoh
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/46f507a261a544359c2ee01e6ca995c1
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spelling	oai:doaj.org-article:46f507a261a544359c2ee01e6ca995c12021-12-02T15:11:53ZBEX2 suppresses mitochondrial activity and is required for dormant cancer stem cell maintenance in intrahepatic cholangiocarcinoma10.1038/s41598-020-78539-02045-2322https://doaj.org/article/46f507a261a544359c2ee01e6ca995c12020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78539-0https://doaj.org/toc/2045-2322Abstract 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.Keiichi TamaiMao Nakamura-ShimaRie Shibuya-TakahashiShin-Ichiro KannoAkira YasuiMai MochizukiWataru IwaiYuta WakuiMakoto AbueKuniharu YamamotoKoh MiuraMasamichi MizumaMichiaki UnnoSadafumi KawamuraIkuro SatoJun YasudaKazunori YamaguchiKazuo SugamuraKennichi SatohNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-15 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Keiichi Tamai Mao Nakamura-Shima Rie Shibuya-Takahashi Shin-Ichiro Kanno Akira Yasui Mai Mochizuki Wataru Iwai Yuta Wakui Makoto Abue Kuniharu Yamamoto Koh Miura Masamichi Mizuma Michiaki Unno Sadafumi Kawamura Ikuro Sato Jun Yasuda Kazunori Yamaguchi Kazuo Sugamura Kennichi Satoh BEX2 suppresses mitochondrial activity and is required for dormant cancer stem cell maintenance in intrahepatic cholangiocarcinoma
description	Abstract 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.
format	article
author	Keiichi Tamai Mao Nakamura-Shima Rie Shibuya-Takahashi Shin-Ichiro Kanno Akira Yasui Mai Mochizuki Wataru Iwai Yuta Wakui Makoto Abue Kuniharu Yamamoto Koh Miura Masamichi Mizuma Michiaki Unno Sadafumi Kawamura Ikuro Sato Jun Yasuda Kazunori Yamaguchi Kazuo Sugamura Kennichi Satoh
author_facet	Keiichi Tamai Mao Nakamura-Shima Rie Shibuya-Takahashi Shin-Ichiro Kanno Akira Yasui Mai Mochizuki Wataru Iwai Yuta Wakui Makoto Abue Kuniharu Yamamoto Koh Miura Masamichi Mizuma Michiaki Unno Sadafumi Kawamura Ikuro Sato Jun Yasuda Kazunori Yamaguchi Kazuo Sugamura Kennichi Satoh
author_sort	Keiichi Tamai
title	BEX2 suppresses mitochondrial activity and is required for dormant cancer stem cell maintenance in intrahepatic cholangiocarcinoma
title_short	BEX2 suppresses mitochondrial activity and is required for dormant cancer stem cell maintenance in intrahepatic cholangiocarcinoma
title_full	BEX2 suppresses mitochondrial activity and is required for dormant cancer stem cell maintenance in intrahepatic cholangiocarcinoma
title_fullStr	BEX2 suppresses mitochondrial activity and is required for dormant cancer stem cell maintenance in intrahepatic cholangiocarcinoma
title_full_unstemmed	BEX2 suppresses mitochondrial activity and is required for dormant cancer stem cell maintenance in intrahepatic cholangiocarcinoma
title_sort	bex2 suppresses mitochondrial activity and is required for dormant cancer stem cell maintenance in intrahepatic cholangiocarcinoma
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/46f507a261a544359c2ee01e6ca995c1
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BEX2 suppresses mitochondrial activity and is required for dormant cancer stem cell maintenance in intrahepatic cholangiocarcinoma

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