CHD8 interacts with BCL11A to induce oncogenic transcription in triple negative breast cancer

Abstract 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.