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Structural basis of DNA-dependent coactivator recruitment by the tuft cell master regulator POU2F3

Aktan Alpsoy1, Jonathan J Ipsaro2, Damianos Skopelitis1

  • 1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.

Cell Reports
|November 19, 2025
PubMed

Insights

Small cell lung cancer (SCLC) tuft cells rely on POU2F3 and its coactivators. Suppressing POU2F3 or OCA-T1 caused tumor regression, revealing a druggable target in SCLC.

Area of Science:

  • Molecular biology
  • Cancer research
  • Structural biology

Background:

  • POU2F3 transcription factor identifies tuft cells and a specific small cell lung cancer (SCLC) subtype.
  • POU2F3 is considered undruggable, but its function depends on OCA-T1 and OCA-T2 coactivators.

Purpose of the Study:

  • To investigate the structural basis and druggability of the POU2F3-OCA-T coactivator dependency in SCLC.
  • To identify potential therapeutic targets within this transcriptional complex.

Main Methods:

  • Crystal structure determination of POU2F3 bound to OCA-T1/OCA-T2 and DNA.
  • Deep mutational scanning of POU2F3 and OCA-T1 to assess variant impact on tumor cell fitness.

Main Results:

  • Acute suppression of POU2F3 or OCA-T1 led to regression of tuft cell-like SCLC xenografts.
  • Crystal structures revealed a tripartite, DNA-dependent interface between POU2F3, OCA-T1/OCA-T2, and DNA.
  • Deep mutational scanning identified mutation-sensitive hotspots and constrained regions critical for tumor cell fitness.

Conclusions:

  • The POU2F3-OCA-T complex integrates DNA recognition with coactivator recruitment.
  • POU2F3-OCA-T represents a structurally tractable vulnerability in tuft cell-like carcinomas, offering a potential therapeutic strategy.
Keywords:
CP: cancerCP: molecular biologyOCA-T1OCA-T2POU2AF2POU2AF3POU2F3X-ray crystallographydeep mutational scanningsmall cell lung cancertuft cell

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