ASXL3 bridges BRD4 to BAP1 complex and governs enhancer activity in small cell lung cancer. ASXL3 bridges BRD4 to BAP1 complex and governs enhancer activity in small cell lung cancer

The bromodomain and extra-terminal (BET) protein BRD4 functions as a transcriptional activator and is a therapeutic target for different human cancers. Here, we report a critical link between Polycomb repressive deubiquitinase-BAP1 (PR-DUB) complex and BRD4, which is bridged by the physical interaction between additional sex combs-like protein 3 (ASXL3) in small cell lung cancer (SCLC). We further showed that ASXL3 functions as an adaptor protein, which directly interacts with BRD4-extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), and maintains chromatin occupancy of BRD4 at active enhancers. Genetic depletion of ASXL3 leads to a genome-wide reduction of histone H3K27Ac levels as well as BRD4 occupancy, resulting in a similar change of gene expression profile induced by BET inhibitors. Pharmacologically-induced inhibition with BET specific chemical degrader (dBET6) selectively inhibits cell proliferation of a subtype of SCLC, characterized with high expression of ASXL3. Collectively, this study provides mechanistic insight into the oncogenic function of ASXL3-BRD4 axis in SCLC. Overall design: To determine gene expression and histone modification change in ASXL3 depleted cells