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APOBEC3 promotes squamous differentiation via IL-1A/AP-1 signaling

Michael S Sturdivant1,2, Andrew S Truong1,2, Mi Zhou1

  • 1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Nature Communications
|December 13, 2025
PubMed

Insights

APOBEC3 enzymes drive urothelial carcinoma progression and squamous differentiation via IL-1α signaling. This finding highlights APOBEC3A

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The APOBEC3 (A3) family of cytidine deaminases is implicated in mutagenesis across various cancers.
  • Urothelial carcinoma of the bladder (UC) exhibits significant mutation burdens attributed to A3 activity, yet its functional role remains understudied.

Purpose of the Study:

  • To investigate the functional role of APOBEC3 in bladder cancer progression and squamous differentiation.
  • To elucidate the molecular mechanisms by which APOBEC3 influences urothelial carcinoma phenotypes.

Main Methods:

  • Development of a genetically engineered murine model (UPPA) with conditional knockout of Pten and Trp53 and overexpression of mouse Apobec3.
  • Analysis of bladder tumors from UPPA mice, including bulk RNA-sequencing of human UC samples.
  • Application of single-cell and spatial transcriptomics to human UC data.

Main Results:

  • Overexpression of mouse Apobec3 in the UPPA model promoted tumor progression and squamous trans-differentiation.
  • APOBEC3-driven squamous differentiation was mediated by IL-1α signaling and downstream AP-1 transcription factor activation.
  • Human APOBEC3A was identified as the sole APOBEC3 family member correlating with squamous differentiation in UC, confirmed by transcriptomic analyses.

Conclusions:

  • Mouse Apobec3 and human APOBEC3A promote squamous differentiation in urothelial carcinoma.
  • IL-1α signaling is a key mediator of APOBEC3-induced trans-differentiation in bladder cancer.
  • Targeting IL-1α signaling, which is amenable to FDA-approved therapies, may offer a therapeutic strategy for APOBEC3-driven UC.

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