RT Journal Article
SR Electronic
T1 BET Inhibitors Target the SCLC-N subtype Small Cell Lung Cancer by Blocking NEUROD1 Transactivation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.10.25.465771
DO 10.1101/2021.10.25.465771
A1 Haobin Chen
A1 Lisa Gesumaria
A1 Young-Kwon Park
A1 Trudy G. Oliver
A1 Dinah S. Singer
A1 Kai Ge
A1 David S. Shrump
YR 2022
UL http://biorxiv.org/content/early/2022/05/11/2021.10.25.465771.abstract
AB Small cell lung cancer (SCLC) is a recalcitrant malignancy that urgently needs new therapies. Four master transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1) are identified in SCLC, and each defines the transcriptome landscape of one molecular subtype. These master factors have not been directly druggable, and targeting their transcriptional coactivator(s) could provide an alternative approach. Here, we identify that BET bromodomain proteins physically interact with NEUROD1 and function as its transcriptional coactivators. Using CRISPR knockout and ChIP-seq, we demonstrate that NEUROD1 plays a critical role in defining the landscapes of BET bromodomain proteins in the SCLC genome. Targeting BET bromodomain proteins by BET inhibitors leads to broad suppression of the NEUROD1-target genes, especially those associated with superenhancers, and reduces 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 targeting transcriptional coactivators could be a novel approach to blocking the master transcription factors in SCLC for therapeutic purposes.Significance Small cell lung cancer (SCLC) is the most aggressive form of lung malignancies, and little progress has been made to improve its outcome in the past two decades. It is now recognized that SCLC is not a single disease but has at least four molecular subtypes, and each subtype features the expression of one master transcription factor. Unfortunately, these master transcription factors are not directly druggable. Here, we identified BET bromodomain proteins as the transcriptional coactivators of NEUROD1, one of the master transcription factors in SCLC. Blocking BET bromodomain proteins with inhibitors suppresses NEUROD1-target genes and reduces tumor growth. Our results demonstrate that blocking transcriptional coactivators could be an alternative approach to targeting the master transcription factors in SCLC.Competing Interest StatementThe authors have declared no competing interest.