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Molecular and functional interactions between AKT and SOX2 in breast carcinoma

Schaefer, Thorsten and Wang, Hui and Mir, Perihan and Konantz, Martina and Pereboom, Tamara C. and Paczulla, Anna M. and Merz, Britta and Fehm, Tanja and Perner, Sven and Rothfuss, Oliver C. and Kanz, Lothar and Schulze-Osthoff, Klaus and Lengerke, Claudia. (2015) Molecular and functional interactions between AKT and SOX2 in breast carcinoma. Oncotarget, 6 (41). pp. 43540-43556.

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Official URL: https://edoc.unibas.ch/62312/

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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.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Stem Cells and Hematopoiesis (Lengerke)
UniBasel Contributors:Lengerke, Claudia
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:1949-2553 (Electronic) 1949-2553 (Linking)
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:24 Nov 2018 11:12
Deposited On:24 Nov 2018 11:12

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