Differentiation signals induce <i>APOBEC3A</i> expression via GRHL3 in squamous epithelia and squamous cell carcinoma
Author(s)
Type
Journal Article
Abstract
Two APOBEC DNA cytosine deaminase enzymes, APOBEC3A and APOBEC3B, generate somatic mutations in cancer, thereby driving tumour development and drug resistance. Here, we used single-cell RNA sequencing to study APOBEC3A and APOBEC3B expression in healthy and malignant mucosal epithelia, validating key observations with immunohistochemistry, spatial transcriptomics and functional experiments. Whereas APOBEC3B is expressed in keratinocytes entering mitosis, we show that APOBEC3A expression is confined largely to terminally differentiating cells and requires grainyhead-like transcription factor 3 (GRHL3). Thus, in normal tissue, neither deaminase appears to be expressed at high levels during DNA replication, the cell-cycle stage associated with APOBEC-mediated mutagenesis. In contrast, in squamous cell carcinoma we find that, there is expansion of GRHL3expression and activity to a subset of cells undergoing DNA replication and concomitant extension of APOBEC3A expression to proliferating cells. These findings suggest that APOBEC3A may play a functional role during keratinocyte differentiation, and offer a mechanism for acquisition of APOBEC3A mutagenic activity in tumours.
Date Issued
2025-01-02
Date Acceptance
2024-10-24
Citation
The EMBO Journal, 2025, 44 (1), pp.1-29
ISSN
0261-4189
Publisher
EMBO Press
Start Page
1
End Page
29
Journal / Book Title
The EMBO Journal
Volume
44
Issue
1
Copyright Statement
© 2024 The Author(s). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Creative Commons Public Domain Dedication waiver http://creativecommons.org/publicdomain/zero/1.0/ applies to the data associated with this article, unless otherwise stated in a credit line to the data, but does not extend to the graphical or creative elements of illustrations, charts, or figures. This waiver removes legal barriers to the re-use and mining of research data. According to standard scholarly practice, it is recommended to provide appropriate citation and attribution whenever technically possible.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/39548236
PII: 10.1038/s44318-024-00298-9
Subjects
ADENOASSOCIATED VIRUS
APOBEC3A
Biochemistry & Molecular Biology
Cancer Mutagenesis
Cell Biology
CYTIDINE DEAMINATION
GRHL3
HNSCC
HYPERMUTATION
Keratinocyte
Life Sciences & Biomedicine
MUTAGENESIS
MUTATIONS
NUCLEAR-DNA
PATHWAY
REGULATORY NETWORK
Science & Technology
SINGLE-CELL
STRAND
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2024-11-15