Related Experiment Video

Updated: Jun 20, 2026

Genome-Wide Mapping of Histone Modifications and Transcription Factor Binding Sites in Neuroendocrine Small Cell Lung Cancer Cell Lines Using CUT&RUN
11:50

Genome-Wide Mapping of Histone Modifications and Transcription Factor Binding Sites in Neuroendocrine Small Cell Lung Cancer Cell Lines Using CUT&RUN

Published on: April 3, 2026

Dual Mechanisms Underlie the Repression of Repressor Element 1-Silencing Transcription Factor Expression in Lung

Koudai Konno1, Hanako Sato-Yazawa1, Jun Ishii1

  • 1Department of Pathology, Dokkyo Medical University School of Medicine and Graduate School of Medicine, Mibu, Japan.

The American Journal of Pathology
|June 18, 2026
PubMed

Insights

Small cell lung carcinoma (SCLC) subtypes differ in gene expression due to REST suppression mechanisms. MicroRNAs and epigenetic changes in SCLC-A/N and LCNEC cells inactivate REST, affecting neuroendocrine gene expression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Small cell lung carcinoma (SCLC) comprises distinct subtypes: ASCL1-predominant (SCLC-A), NEUROD1-predominant (SCLC-N), and POU2F3 (SCLC-P).
  • SCLC-A and SCLC-N, along with large cell neuroendocrine carcinoma (LCNEC), express chromogranin A (CHGA) and synaptophysin (SYP), unlike SCLC-P.
  • RE1-silencing transcription factor (REST) regulates CHGA and SYP expression, and its suppression mechanisms in neuroendocrine carcinoma (NEC) are key to understanding subtype differences.

Purpose of the Study:

  • Investigate the mechanisms of REST suppression in NEC.
  • Determine the causes for differential CHGA and SYP expression between SCLC subtypes.
  • Elucidate the roles of microRNAs and epigenetics in REST regulation within NEC.

Main Methods:

  • Analysis of SCLC subtypes (SCLC-A, SCLC-N, SCLC-P) and LCNEC.
  • Investigated microRNA regulation of REST using mRNA binding assays.
  • Employed bisulfite sequencing, DNA methyltransferase inhibitors, histone deacetylase inhibitors, and ChIP-qPCR to assess epigenetic modifications.

Main Results:

  • miR-375-3p, induced by ASCL1 and NEUROD1, represses REST expression by targeting REST mRNA.
  • SCLC-A/N and LCNEC cells exhibit REST gene inactivation via promoter/enhancer hypermethylation and histone deacetylation.
  • These epigenetic changes correlate with high ASCL1 and NEUROD1 expression in SCLC-A/N and LCNEC.

Conclusions:

  • NEC exhibits dual REST repression mechanisms involving both microRNAs and epigenetics.
  • These regulatory pathways lead to strict control over CHGA, SYP, and other neuroendocrine-specific genes.
  • Understanding these mechanisms is crucial for SCLC and LCNEC subtyping and targeted therapies.

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