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BET Inhibitors Target the SCLC-N Subtype of Small-Cell Lung Cancer by Blocking NEUROD1 Transactivation.

Publication ,  Journal Article
Chen, H; Gesumaria, L; Park, Y-K; Oliver, TG; Singer, DS; Ge, K; Schrump, DS
Published in: Mol Cancer Res
February 1, 2023

UNLABELLED: 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.

Duke Scholars

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Published In

Mol Cancer Res

DOI

EISSN

1557-3125

Publication Date

February 1, 2023

Volume

21

Issue

2

Start / End Page

91 / 101

Location

United States

Related Subject Headings

  • Transcriptional Activation
  • Transcription Factors
  • Small Cell Lung Carcinoma
  • Oncology & Carcinogenesis
  • Lung Neoplasms
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Developmental Biology
  • Cell Line, Tumor
  • Basic Helix-Loop-Helix Transcription Factors
 

Citation

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Chen, H., Gesumaria, L., Park, Y.-K., Oliver, T. G., Singer, D. S., Ge, K., & Schrump, D. S. (2023). BET Inhibitors Target the SCLC-N Subtype of Small-Cell Lung Cancer by Blocking NEUROD1 Transactivation. Mol Cancer Res, 21(2), 91–101. https://doi.org/10.1158/1541-7786.MCR-22-0594
Chen, Haobin, Lisa Gesumaria, Young-Kwon Park, Trudy G. Oliver, Dinah S. Singer, Kai Ge, and David S. Schrump. “BET Inhibitors Target the SCLC-N Subtype of Small-Cell Lung Cancer by Blocking NEUROD1 Transactivation.Mol Cancer Res 21, no. 2 (February 1, 2023): 91–101. https://doi.org/10.1158/1541-7786.MCR-22-0594.
Chen H, Gesumaria L, Park Y-K, Oliver TG, Singer DS, Ge K, et al. BET Inhibitors Target the SCLC-N Subtype of Small-Cell Lung Cancer by Blocking NEUROD1 Transactivation. Mol Cancer Res. 2023 Feb 1;21(2):91–101.
Chen, Haobin, et al. “BET Inhibitors Target the SCLC-N Subtype of Small-Cell Lung Cancer by Blocking NEUROD1 Transactivation.Mol Cancer Res, vol. 21, no. 2, Feb. 2023, pp. 91–101. Pubmed, doi:10.1158/1541-7786.MCR-22-0594.
Chen H, Gesumaria L, Park Y-K, Oliver TG, Singer DS, Ge K, Schrump DS. BET Inhibitors Target the SCLC-N Subtype of Small-Cell Lung Cancer by Blocking NEUROD1 Transactivation. Mol Cancer Res. 2023 Feb 1;21(2):91–101.

Published In

Mol Cancer Res

DOI

EISSN

1557-3125

Publication Date

February 1, 2023

Volume

21

Issue

2

Start / End Page

91 / 101

Location

United States

Related Subject Headings

  • Transcriptional Activation
  • Transcription Factors
  • Small Cell Lung Carcinoma
  • Oncology & Carcinogenesis
  • Lung Neoplasms
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Developmental Biology
  • Cell Line, Tumor
  • Basic Helix-Loop-Helix Transcription Factors