Waterhouse Mark, Lazarus Kyren, Santolla Maria Francesca, Pensa Sara, Williams Eleanor, Siu Abigail J Q, Mohammed Hisham, Mohorianu Irina, Maggiolini Marcello, Carroll Jason, Itzhaki Laura S, Rahman Taufiq, Khaled Walid T
Department of Pharmacology, University of Cambridge, CB2 1PD, Cambridge, UK.
Cambridge Stem Cell Institute, University of Cambridge, CB2 0AW, Cambridge, UK.
EMBO J. 2025 May 6. doi: 10.1038/s44318-025-00447-8.
The identification of tumour-specific protein-protein interactions remains a challenge for the development of targeted cancer therapies. In this study we describe our approach for the identification of triple negative breast cancer (TNBC)-specific protein-protein interactions focusing on the oncogene BCL11A. We used a proteomic approach to identify the BCL11A protein networks in TNBC and compared it to its network in B-cells, a cell type in which BCL11A plays crucial roles. This approach identified the chromatin remodeller CHD8 as a TNBC-specific interaction partner of BCL11A. We show that CHD8 also plays a key role in TNBC pathogenesis, with detailed multi-omics analysis revealing that BCL11A and CHD8 co-regulate several targets and synergise to drive tumour development and progression. Using a battery of biophysical assays, we confirm that the BCL11A-CHD8 interaction is direct and identify chemical fragments that disrupt this interaction and affect downstream targets, decreasing proliferation in 3D colony assays. Our study provides a proof-of-principle approach for investigating tumour-specific protein-protein interactions and identifies lead chemical compounds that could be developed into novel therapeutics for TNBC.
鉴定肿瘤特异性蛋白质-蛋白质相互作用仍然是靶向癌症治疗发展面临的一项挑战。在本研究中，我们描述了我们用于鉴定三阴性乳腺癌（TNBC）特异性蛋白质-蛋白质相互作用的方法，重点关注癌基因BCL11A。我们采用蛋白质组学方法鉴定TNBC中的BCL11A蛋白质网络，并将其与BCL11A发挥关键作用的细胞类型B细胞中的网络进行比较。该方法鉴定出染色质重塑因子CHD8是BCL11A在TNBC中的特异性相互作用伴侣。我们表明，CHD8在TNBC发病机制中也起关键作用，详细的多组学分析显示，BCL11A和CHD8共同调节多个靶点并协同作用以驱动肿瘤发展和进展。通过一系列生物物理测定，我们证实BCL11A-CHD8相互作用是直接的，并鉴定出破坏这种相互作用并影响下游靶点、降低三维集落测定中增殖的化学片段。我们的研究为研究肿瘤特异性蛋白质-蛋白质相互作用提供了一种原理验证方法，并鉴定出可开发为TNBC新型疗法的先导化合物。
