Molecular and functional interactions between AKT and SOX2 in breast carcinoma.

Thorsten Schaefer,Klaus Schulze-Osthoff,Martina Konantz,Oliver C Rothfuss,Tamara C Pereboom,Perihan Mir,Lothar Kanz,Claudia Lengerke,Tanja Fehm,Hui Wang,Anna M Paczulla,Britta Merz,Sven Perner

doi:10.18632/oncotarget.6183

Abstract

The transcription factor SOX2 is a key regulator of pluripotency in embryonic stem cells and plays important roles in early organogenesis. Recently, SOX2 expression was documented in various cancers and suggested as a cancer stem cell (CSC) marker. Here we identify the Ser/Thr-kinase AKT as an upstream regulator of SOX2 protein turnover in breast carcinoma (BC). SOX2 and pAKT are co-expressed and co-regulated in breast CSCs and depletion of either reduces clonogenicity. Ectopic SOX2 expression restores clonogenicity and in vivo tumorigenicity of AKT-inhibited cells, suggesting that SOX2 acts as a functional downstream AKT target. Mechanistically, we show that AKT physically interacts with the SOX2 protein to modulate its subcellular distribution. AKT kinase inhibition results in enhanced cytoplasmic retention of SOX2, presumably via impaired nuclear import, and in successive cytoplasmic proteasomal degradation of the protein. In line, blockade of either nuclear transport or proteasomal degradation rescues SOX2 expression in AKT-inhibited BC cells. Finally, AKT inhibitors efficiently suppress the growth of SOX2-expressing putative cancer stem cells, whereas conventional chemotherapeutics select for this population. Together, our results suggest the AKT/SOX2 molecular axis as a regulator of BC clonogenicity and AKT inhibitors as promising drugs for the treatment of SOX2-positive BC.

Highlights

Pluripotency-associated proteins like SOX2 and OCT4 are key regulators of embryonic stem cells and foster the reprogramming of terminally differentiated somatic cells back to a pluripotent stem cell state [1]
MCF7 cells displaying a high endogenous SOX2 expression were treated with two specific SOX2 shRNAs or respective control GFP-lentiviral particles and correctly transduced cells were isolated by flow cytometry
Spheres formation was only observed from SOX2-induced T47D cells, whereas mock-treated control cells were only able to associate in irregularly shaped aggregates (Figure 1F and Supplementary Figure 3)

Summary

Introduction

Pluripotency-associated proteins like SOX2 and OCT4 are key regulators of embryonic stem cells and foster the reprogramming of terminally differentiated somatic cells back to a pluripotent stem cell state [1]. SOX2 expression in BC is mostly confined to a minor subset of tumor cells and detectable at early stages of the disease as well as at relapse, suggesting that www.impactjournals.com/oncotarget it is involved in BC stem cell biology and might represent a genetic driver event [14, 16]. Another major molecular regulator of both embryonic and cancer stem cell self-renewal is the kinase AKT. Inhibition of AKT was shown to affect cancer stem cell populations including breast CSCs [21, 22], the underlying molecular details remain largely unknown

Methods

Results

Conclusion