Small cell lung cancer (SCLC) is a recalcitrant malignancy that urgently needs new therapies. Four master transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1) have been identified in SCLC, and each defines the transcriptome landscape of one molecular subtype. However, these master transcription factors have not been found directly druggable. We hypothesized that blocking their transcriptional coactivator(s) could provide an alternative approach to target these master transcription factors. Here, we identify that BET proteins physically interact with NEUROD1 and function as transcriptional coactivators. Using CRISPR knockout and ChIP-seq, we demonstrate that NEUROD1 plays a critical role in defining the landscapes of BET proteins in the SCLC genome. Blocking BET proteins by inhibitors led to broad suppression of the NEUROD1-target genes, especially those associated with superenhancers, resulting in the inhibition of SCLC growth in vitro and in vivo. LSAMP, a membrane protein in the IgLON family, was identified as one of the NEUROD1-target genes mediating BET inhibitor sensitivity in SCLC. Altogether, our study reveals that BET proteins are essential in regulating NEUROD1 transactivation and are promising targets in SCLC-N subtype tumors. Implications: Our findings suggest that targeting transcriptional coactivators could be a novel approach to blocking the master transcription factors in SCLC for therapeutic purposes.
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 the function and transactivation of NEUROD1 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 SCLC 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.
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