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Peer-Reviewed Publication
Cell Rep2025;44(11):116572.November 25, 2025Journal Article

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

Aktan Alpsoy1, Jonathan J Ipsaro2, Damianos Skopelitis1, Sujay Pal1, Frank S Chung3, Shannon Carpenter3, John J Desmarais1, Xiaoli S Wu1, Kenneth Chang1, Matthew T DiMare3, Erin Harten3, Staci Bergman3, Justin B Kinney1, Jeffrey A Engelman3, Hyo-Eun C Bhang3, Leemor Joshua-Tor4, Christopher R Vakoc5
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
2Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Howard Hughes Medical Institute, W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
3Treeline Biosciences, Watertown, MA 02472, USA.
4Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Howard Hughes Medical Institute, W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: leemor@cshl.edu.
5Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: vakoc@cshl.edu.
PubMed PMC DOI PDF

Abstract

The transcription factor POU2F3 defines the identity of tuft cells and underlies a distinct molecular subtype of small cell lung cancer (SCLC). Although POU2F3 is considered undruggable, its activity critically depends on the coactivators OCA-T1 and OCA-T2. Here, we demonstrate that acute suppression of either POU2F3 or OCA-T1 induces regression of tuft cell-like SCLC xenografts in vivo. To explor…

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