Abstract 255: Redefining SOX2 as a bifunctional mediator of transcription and adjusted translation control

Abstract The vertebrate transcription factor SOX2 (SRY Homology Box 2) is essential for stem cell maintenance, a prominent (co)inductor of pluripotency in reprogramming technology, and an oncogenic driver of transformation, therapy resistance, and disease relapse in cancer. These cell fate discriminatory events are currently understood as SOX2-imposed changes in DNA activity and the resultant co-transcriptional rewiring inside the cell’s nucleus. Cytoplasmic forms of SOX2, on the other hand, receive comparatively little scientific attention and are typically marginalized as a molecular reservoir for nuclear entry. We now challenge this notion as we identify further cell fate discriminatory significance selectively within the cytoplasmic pool of SOX2. Specifically, we find extra-nuclear forms of SOX2 in physical association with the ribosome where they modulate the translation rate of selected, SOX2-imposed mRNAs in the cytosol. These translational adaptations occur independent of nuclear structures or DNA and involve protein segments that have no DNA-binding capacity on their own. Very intriguingly, whereas transcriptional SOX2 targets impose stemness and pluripotency phenotypes, the newly identified co-translational targets predominantly relate to morphogenesis and differentiation events. This matches natural expression patterns in early ontogenesis, where SOX2 stains the nuclei of the inner cell mass (i.e., embryonic stem cells, ESCs), but the cytosol of the surrounding trophectoderm (i.e., differentiating non-stem cells). Most importantly though, we find the ribosome modulatory activity of SOX2 functionally abolished by a disease-linked human polymorphism, indicating a (patho)physiological relevance of our discovery. Taken together, we present experimental evidence that redefines SOX2 as a bifunctional modulator of transcription and translation control, which may pave the way for further refinements in reprogramming technology and the fight against cancer. Citation Format: Nitish Mittal, Meric Ataman, Hui Wang, Silvia Candido, Jonas Lötscher, Sergiy Velychko, Lionel Tintignac, Thomas Bock, Anastasiya Börsch, Jochen Baßler, Tata Nageswara Rao, Jakub Zmajkovic, Sarah Roffeis, Jordan Löliger, Francis Jacob, Alain Dumlin, Christoph Schürch, Alexander Schmidt, Radek C. Skoda, Christoph Hess, Hans R. Schöler, Holm Zaehres, Ed Hurt, Mihaela Zavolan, Claudia Lengerke, Thorsten Schaefer. Redefining SOX2 as a bifunctional mediator of transcription and adjusted translation control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 255.