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

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

doi:10.18632/oncotarget.26583

Masami Nozaki, Ayumi Okamoto + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.26583

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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.

Highlights

Cancer stem cells (CSCs), called tumorinitiating cells (TICs), drive tumorigenesis and tumor heterogeneity through their abilities to self-renew and generate tumorigenic progeny
Expression of Scribble was maintained at comparatively high levels during the early stage and decreased slightly after the pre-SR stage, but did not dramatically oscillate between stages of sphere formation like LATS and TAZ (Figures 4D, seventh panel; 2A, fourth panel). These results suggest that phosphorylation and activation of LATS1/2 and SNAIL are required for initiation of self-renewal during sphere formation by CSCs, whereas dephosphorylation and inactivation of these proteins might be required for the maintenance of sphere formation during later stages
We demonstrated that LATS1/2 are essential for self-renewal of oral squamous cell carcinoma (OSCC) cells with CSC properties, probably via activation of SNAIL and TAZ

Summary

Introduction

Cancer stem cells (CSCs), called tumorinitiating cells (TICs), drive tumorigenesis and tumor heterogeneity through their abilities to self-renew and generate tumorigenic progeny. A study using a knock-in reporter mouse line for Snail (Snail-YFP) demonstrated that breast TICs expressing Snail undergo the EMT [12] These findings imply that, through activation of EMT-TFs, especially SNAIL, the EMT is a leading cause of cancer stemness in a variety of tumors [13, 14, 15]. Diverse signaling pathways, including Hippo, WNT, SHH (sonic hedgehog), NOTCH, and the DNA damage response (DDR), are involved in CSC properties and the EMT [16, 17, 18, 19, 20, 21] These studies have advanced our understanding, the molecular mechanisms underlying CSC-specific properties, especially their capacity to initiate and maintain self-renewal, have yet to be fully elucidated

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