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Publications

Journal Article Ppublish

PubMed: 40595415 DOI: 10.1038/s41388-025-03481-2

Integrative epigenome and transcriptome analyses reveal transcriptional programs differentially regulated by ASCL1 and NEUROD1 in small cell lung cancer.

Oncogene 44(34):3113-3125

Authors: Hiroshi Takumida, Akira Saito, Yugo Okabe, Yasuhiro Terasaki, Yu Mikami, Hidenori Tanaka, Masami Suzuki, Yu Hamaguchi, Chao Zeng, Michiaki Hamada, Hiroshi I Suzuki, Hidenori Kage, Masafumi Horie

Affiliations

  • Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
  • Department of Analytic Human Pathology, Nippon Medical School, Tokyo, 113-8603, Japan.
  • Division of Pathology, Nippon Medical School Hospital, Tokyo, 113-8603, Japan.
  • Department of Otorhinolaryngology-Head and Neck Surgery, Graduate School of Medicine, The University of Osaka, Osaka, 565-0871, Japan.
  • Faculty of Science and Engineering, Waseda University, Tokyo, 169-8555, Japan.
  • Faculty of Science and Engineering, Waseda University, Tokyo, 169-8555, Japan. AIST-Waseda University Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology, Tokyo, 169-8555, Japan.
  • AIST-Waseda University Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology, Tokyo, 169-8555, Japan.
  • Division of Molecular Oncology, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan. Institute for Glyco-core Research (iGCORE), Nagoya University, Nagoya, 464-8601, Japan. Center for One Medicine Innovative Translational Research (COMIT), Nagoya University, Nagoya, 464-8601, Japan. Inamori Research Institute for Science (InaRIS), Kyoto, 600-8411, Japan.
  • Department of Molecular and Cellular Pathology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, 920-0934, Japan.
  • Division of Molecular and Genomic Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan.

Abstract

Small cell lung cancer (SCLC), an aggressive neuroendocrine carcinoma, has an extremely poor prognosis. ASCL1 and NEUROD1 are key regulators of neuroendocrine features, and previous studies have suggested that SCLC plasticity occurs during the transition from ASCL1-positive (SCLC-A) to NEUROD1-positive (SCLC-N) subtypes. In this study, we attempted to understand the transcriptional programs governed by ASCL1 and NEUROD1 to identify markers of SCLC plasticity. Immunohistochemistry and epigenome and transcriptome analyses in ASCL1/NEUROD1 double-positive SCLC cells (SCLC-A/N) revealed co-expression of ASCL1 and NEUROD1 in almost half of SCLC cases. Genome-wide profiling of histone modifications, ASCL1 and NEUROD1 binding sites, and gene co-expression patterns revealed that both ASCL1 and NEUROD1 are active in SCLC-A/N and regulate partially distinct target genes. Furthermore, SCLC-A/N exhibited characteristics that were intermediate between SCLC-A and SCLC-N subtypes. NEUROD1 knockout, followed by RNA-seq, suggested an association between NEUROD and NHLH transcription factors that might shape the NEUROD1-mediated regulatory network. Small RNA-seq further indicated that miR-139-5p is specifically expressed in NEUROD1-positive SCLC, and transcriptomic studies suggested that miR-139-5p might regulate an array of pathologically relevant genes in collaboration with other NEUROD1-associated miRNAs. Our integrative analyses provide deeper insights into SCLC heterogeneity and multi-layered transcriptional programs differentially governed by ASCL1 and NEUROD1.

MeSH

Oncogenes, Cells, Genes, Gene Expression Profiling, Lung, Transcriptome, Neoplasms, Lung Neoplasms, Small Cell Lung Carcinoma, Epigenome