SCLC is a recalcitrant malignancy with a dismal prognosis. Four molecular subtypes of SCLC have been named, each associated with one master transcription factor (ASCL1, NEUROD1, POU2F3, or YAP1). Much is still unknown about NEUROD1s function and transactivation in this malignancy. Herein we report that knockout of NEUROD1 triggered SCLC to evolve into a YAP1 subtype. Through an integrated analysis of RNA-seq and ChIP-seq, we found NEUROD1 regulates neural-related genes by binding to gene promoters and distal enhancers. NEUROD1 physically interacts with BET bromodomain proteins and recruits them to actively transcribed genes. Inhibition of BET bromodomain proteins blocks NEUROD1 transactivation and suppresses SCLC growth. We identified LSAMP as one of the NEUROD1-target genes that mediate SCLCs sensitivity to BET bromodomain inhibitors. Our findings suggest that targeting transcriptional coactivators could be a new approach to block master transcription factors in SCLC to enable precision therapy.
