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

## TL;DR

APOBEC3 enzymes drive squamous cell changes in bladder cancer through IL-1α and AP-1 signaling, offering new insights into cancer progression.

## Contribution

This study reveals a novel functional role of APOBEC3 in promoting squamous trans-differentiation in bladder cancer via IL-1α/AP-1 signaling.

## Key findings

- Mouse Apobec3 and human APOBEC3A promote squamous differentiation in urothelial carcinoma.
- APOBEC3A is the only human APOBEC3 family member correlated with squamous differentiation in UC.
- IL-1α signaling mediates APOBEC3-driven squamous trans-differentiation in bladder cancer.

## Abstract

The APOBEC3 family of RNA and single stranded DNA cytidine deaminases contribute prominently to the mutagenesis of certain cancers including urothelial carcinoma of the bladder (UC). Remarkably, up to 70% of mutations in UC are attributable to the mutagenic activity of the APOBEC3 deaminases. Despite this strong association, few functional studies have investigated APOBEC3’s role in bladder cancer. We report a genetically engineered murine model with conditional knock out of Pten and Trp53 in addition to overexpression of mouse Apobec3 (UPPA). Analysis of bladder tumors from UPPA mice demonstrates that mA3 promotes tumor progression and squamous trans-differentiation. We establish that APOBEC3 promotes squamous differentiation through IL-1α and downstream activation of the AP-1 transcription factor. Bulk RNA-sequencing from human UC shows APOBEC3A as the only human APOBEC3 family member to correlate with squamous differentiation. Furthermore, single cell and spatial transcriptomics reinforces the role of APOBEC3A in fostering squamous trans-differentiation and promoting the emergence of a subpopulation of highly squamous epithelial cells. Our results demonstrate that mouse Apobec3 and human APOBEC3A promote squamous differentiation in urothelial carcinoma and that this trans-differentiation phenotype is mediated through IL-1α signaling, a target of FDA approved therapies for rheumatologic disease.

Deaminases of the APOBEC3 family contribute to the mutagenesis of various cancers, including urothelial carcinoma (UC) of the bladder. Here, the authors use functional studies and transcriptomics to demonstrate that APOBEC3 promotes tumour progression and squamous trans-differentiation in UC through IL-1α and downstream activation of the AP-1 transcription factor.