Abstract 3023: Master corepressor inactivation through oncogene suppressor RAI2 mediated polymerization

Abstract Imbalanced transcription of a large number of genes can be caused at various levels, ranging from alterations in individual transcription factors to dysfunctional corepressor and coactivator complexes [1]. C-terminal binding proteins (CtBPs) are ubiquitous master transcriptional coregulators associated with the Polycomb Repressive Complex 2 (PRC2), with essential functions in the development and oncogenesis of various tumor entities, including breast cancer and prostate cancer (PC) [2,3]. As CtBPs bind to short linear PxDLS-like sequence motifs (SLiMs), the presence of such motifs in tandem on the putative metastasis suppressor RAI2 [4] suggested a previously undiscovered dual interaction with CtBPs. Here, we show that RAI2 induces CtBP polymerization through well-ordered filaments of stacked tetrameric CtBP layers, as illustrated by a high-resolution single particle cryo electron microscopy structure. These filaments are mirrored by RAI2-mediated CtBP nuclear foci and relief of CtBP corepressor function in RAI2-expressing cancer cells. Analyses of a diverse PC patient cohort revealed a substantial decrease in RAI2 in the aggressive subtypes, suggesting a pivotal role of RAI2 in the transition to androgen receptor signaling-independent progression. Taken together, our data demonstrate a previously unknown mechanism of multivalent short linear sequence motif-induced polymerization. As RAI2-like SLiM motifs are found in a wide range of organisms, including pathogenic viruses, our findings serve as a paradigm for diverse functional effects through multivalent interaction-mediated polymerization by disordered proteins in healthy and diseased conditions. The specific properties of these repeated interactions open up new therapeutic opportunities. References [1] Lee, T.I. & Young, R.A. Transcriptional regulation and its misregulation in disease. Cell 152, 1237-51 (2013). [2] Di, L.J. et al. Genome-wide profiles of CtBP link metabolism with genome stability and epithelial reprogramming in breast cancer. Nat Commun 4, 1449 (2013). [3] Wang, R. et al. Role of transcriptional corepressor CtBP1 in prostate cancer progression. Neoplasia 14, 905-14 (2012). [4] Werner, S. et al. Suppression of early hematogenous dissemination of human breast cancer cells to bone marrow by retinoic Acid-induced 2. Cancer Discov 5, 506-19 (2015). Citation Format: Nishit Goradia, Stefan Werner, Edukondalu Mullapudi, Gunhild von Amsberg, Klaus Pantel, Matthias Wilmanns. Master corepressor inactivation through oncogene suppressor RAI2 mediated polymerization [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 3023.