Oncotarget

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LATS1/2 kinases trigger self-renewal of cancer stem cells in aggressive oral cancer

Masami Nozaki, Norikazu Yabuta _, Moe Fukuzawa, Satomi Mukai, Ayumi Okamoto, Towa Sasakura, Kohshiro Fukushima, Yoko Naito, Gregory D. Longmore and Hiroshi Nojima

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Oncotarget. 2019; 10:1014-1030. https://doi.org/10.18632/oncotarget.26583

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Abstract

Masami Nozaki1,*, Norikazu Yabuta2,4,*, Moe Fukuzawa2, Satomi Mukai2,5, Ayumi Okamoto2, Towa Sasakura2, Kohshiro Fukushima2, Yoko Naito2,6, Gregory D. Longmore3 and Hiroshi Nojima2

1Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan

2Department of Molecular Genetics, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan

3ICCE Institute, Washington University, St Louis, MO 63110, USA

4Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan

5Division of Cancer Biology, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya City, Aichi 464-8681, Japan

6Division of Cancer Cell Regulation, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya City, Aichi 464-8681, Japan

*These authors have contributed equally to this work

Correspondence to:

Norikazu Yabuta, email: nyabuta@biken.osaka-u.ac.jp

Keywords: Hippo pathway; LATS; SNAIL; oral cancer; cancer stem cells (CSCs)

Received: September 20, 2018     Accepted: December 27, 2018     Published: February 01, 2019

ABSTRACT

Cancer stem cells (CSCs), which play important roles in tumor initiation and progression, are resistant to many types of therapies. However, the regulatory mechanisms underlying CSC-specific properties, including self-renewal, are poorly understood. Here, we found that LATS1/2, the core Hippo pathway-kinases, were highly expressed in the oral squamous cell carcinoma line SAS, which exhibits high capacity of CSCs, and that depletion of these kinases prevented SAS cells from forming spheres under serum-free conditions. Detailed examination of the expression and activation of LATS kinases and related proteins over a time course of sphere formation revealed that LATS1/2 were more highly expressed and markedly activated before initiation of self-renewal. Moreover, TAZ, SNAIL, CHK1/2, and Aurora-A were expressed in hierarchical, oscillating patterns during sphere formation, suggesting that the process consists of four sequential steps. Our results indicate that LATS1/2 trigger self-renewal of CSCs by regulating the Hippo pathway, the EMT, and cell division.


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