Transcriptional addiction in cancer cells is mediated by YAP/TAZ through BRD4

Cancer cells rely on dysregulated gene expression. This establishes specific transcriptional addictions that may be therapeutically exploited. Yet, the mechanisms ultimately responsible for these addictions are poorly understood. Here we investigated the transcriptional dependencies of transformed cells to transcription factors YAP and TAZ. YAP/TAZ physically engage the general coactivator BRD4, dictating the genome-wide association of BRD4 to chromatin. YAP/TAZ flag a large set of enhancers with super-enhancer-like functional properties. YAP/TAZ-bound enhancers mediate recruitment of BRD4 and Pol II at YAP/TAZ-regulated promoters, boosting expression of a host of growth-regulating genes. Treatment with small molecule inhibitors of BRD4 blunts YAP/TAZ pro-tumorigenic activity in several cell/tissue contexts, causes regression of pre-established, YAP/TAZ-addicted neoplastic lesions, and reverts drug resistance. This work sheds light on essential mediators, mechanisms and genome-wide regulatory elements responsible for transcriptional addiction in cancer and lays the groundwork for a rational use of BET inhibitors according to YAP/TAZ biology.