The stem cell/cancer stem cell marker ALDH1A3 regulates the expression of the survival factor tissue transglutaminase, in mesenchymal glioma stem cells.

Kelly E Sullivan,Kathy Rojas,Kristin F Wilson,Richard A Cerione,Ichiro Nakano

doi:10.18632/oncotarget.16479

Kelly E Sullivan, Kathy Rojas + Show 3 more

Open Access

https://doi.org/10.18632/oncotarget.16479

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Abstract

Tissue transglutaminase (tTG), a dual-function enzyme with GTP-binding and acyltransferase activities, has been implicated in the survival and chemotherapy resistance of aggressive cancer cells and cancer stem cells, including glioma stem cells (GSCs). Using a model system comprising two distinct subtypes of GSCs referred to as proneural (PN) and mesenchymal (MES), we find that the phenotypically aggressive and radiation therapy-resistant MES GSCs exclusively express tTG relative to PN GSCs. As such, the self-renewal, proliferation, and survival of these cells was sensitive to treatment with tTG inhibitors, with a benefit being observed when combined with the standard of care for high grade gliomas (i.e. radiation or temozolomide). Efforts to understand the molecular drivers of tTG expression in MES GSCs revealed an unexpected link between tTG and a common marker for stem cells and cancer stem cells, Aldehyde dehydrogenase 1A3 (ALDH1A3). ALDH1A3, as well as other members of the ALDH1 subfamily, can function in cells as a retinaldehyde dehydrogenase to generate retinoic acid (RA) from retinal. We show that the enzymatic activity of ALDH1A3 and its product, RA, are necessary for the observed expression of tTG in MES GSCs. Additionally, the ectopic expression of ALDH1A3 in PN GSCs is sufficient to induce the expression of tTG in these cells, further demonstrating a causal link between ALDH1A3 and tTG. Together, these findings ascribe a novel function for ALDH1A3 in an aggressive GSC phenotype via the up-regulation of tTG, and suggest the potential for a similar role by ALDH1 family members across cancer types.

Highlights

Tissue transglutaminase is a dual-function GTP-binding protein/crosslinking enzyme which has been previously linked to the development of aggressive cancers
We found that disabling the acyltransferase activity of Tissue transglutaminase (tTG) with each of these inhibitors blocked the ability of the MES glioma stem cells (GSCs) cell lines 13 and 326 to form neurospheres, thereby preventing the cells from undergoing self-renewal (Figure 2A)
We demonstrated that GSCs could be subtyped based on their gene expression profiles into two classes, proneural (PN) and mesenchymal (MES), with the CD44+ MES GSCs showing a markedly more aggressive phenotype and radio-resistance relative to PN GSCs [10]

Summary

Introduction

Tissue transglutaminase (tTG) is a dual-function GTP-binding protein/crosslinking enzyme which has been previously linked to the development of aggressive cancers. TTG has been implicated in the survival and proliferation of CD44+ glioma stem cells (GSCs), as well as the survival, migration, invasion, and self-renewal of epidermal squamous cell carcinoma stem cells [8,9]. Building on these studies and our previous characterization of tTG in glioblastoma cell lines, we sought to further understand the role of tTG in high grade gliomas (HGGs), in GSCs, as well as how it may be therapeutically targeted, and the mechanism for its up-regulated expression in cancer stem cell (CSC) populations. We were interested in determining how tTG expression is induced in MES GSCs

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