Differentiation signals induce APOBEC3A expression via GRHL3 in squamous epithelia and squamous cell carcinoma

Smith, Nicola J, Reddin, Ian, Policelli, Paige, Oh, Sunwoo, Zainal, Nur, Howes, Emma, Jenkins, Benjamin, Tracy, Ian, Edmond, Mark, Sharpe, Benjamin, and others. (2025) Differentiation signals induce APOBEC3A expression via GRHL3 in squamous epithelia and squamous cell carcinoma. The EMBO journal, 44 (1). pp. 1-29. ISSN 0261-4189. E-ISSN 1460-2075. (doi:10.1038/s44318-024-00298-9) (KAR id:107987)

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Official URL: https://doi.org/10.1038/s44318-024-00298-9

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.

Item Type:	Article
DOI/Identification number:	10.1038/s44318-024-00298-9
Uncontrolled keywords:	Keratinocyte, Cancer Mutagenesis, APOBEC3A, GRHL3, HNSCC
Subjects:	Q Science Q Science > QH Natural history > QH301 Biology
Divisions:	Divisions > Division of Natural Sciences > Biosciences
Funders:	Biotechnology and Biological Sciences Research Council (https://ror.org/00cwqg982) Rosetrees Trust (https://ror.org/04e3zg361) Cancer Research UK (https://ror.org/054225q67) National Cancer Institute (https://ror.org/04w2jh416) AstraZeneca (United Kingdom) (https://ror.org/04r9x1a08) National Institute for Health Research (https://ror.org/0187kwz08)
SWORD Depositor:	JISC Publications Router
Depositing User:	JISC Publications Router
Date Deposited:	29 Jan 2025 16:14 UTC
Last Modified:	30 Jan 2025 09:38 UTC
Resource URI:	https://kar.kent.ac.uk/id/eprint/107987 (The current URI for this page, for reference purposes)

University of Kent Author Information

Smith, Nicola J.

Creator's ORCID:	https://orcid.org/0009-0004-9940-1070
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