Plasticity of lung cancer stem-like cells is regulated by the transcription factor HOXA5 that is induced by oxidative stress
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Hiroshi Saijo1,2, Yoshihiko Hirohashi1, Toshihiko Torigoe1, Ryota Horibe1,2, Akari Takaya1, Aiko Murai1, Terufumi Kubo1, Toshimitsu Kajiwara1, Tsutomu Tanaka1, Yosuke Shionoya1,2, Eri Yamamoto1, Reo Maruyama3, Munehide Nakatsugawa1, Takayuki Kanaseki1, Tomohide Tsukahara1, Yasuaki Tamura1,4, Yasushi Sasaki5, Takashi Tokino5, Hiromu Suzuki3, Toru Kondo6, Hiroki Takahashi2, Noriyuki Sato1
1Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, 060-8556, Japan
2Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, 060-8556, Japan
3Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, 060-8556, Japan
4Department of Molecular Therapeutics, Center for Food and Medical Innovation, Hokkaido University, Sapporo, 060-8638, Japan
5Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, 060-8556, Japan
6Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, 060-8638, Japan
Yoshihiko Hirohashi, email: [email protected]
Toshihiko Torigoe, email: [email protected]
Keywords: cancer stem cell, plasticity, lung cancer, SOX2, HOXA5
Received: August 26, 2015 Accepted: June 26, 2016 Published: July 13, 2016
Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are reasonable targets for cancer therapy. However, recent studies have revealed that some non-CSCs/CICs have plastic ability and can dedifferentiate into CSCs/CICs. Therefore, an understanding of the molecular mechanisms that control the plasticity is essential to achieve CSC/CIC-targeting therapy. In this study, we analyzed the plasticity of lung cancer cells and found that lung non-CSCs/CICs can dedifferentiate into CSCs/CICs in accordance with the expression of stem cell transcription factor SOX2. SOX2 expression was induced by the transcription factor HOXA5. Oxidative stress repressed the expression of HDAC8 and then induced histone 3 acetylation and increased the expression of HOXA5 and SOX2. These findings indicate that lung cancer cells have plasticity under a condition of oxidative stress and that HOAX5 has a critical role in dedifferentiation.
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