Differentiation signals induce APOBEC3A expression via GRHL3 in squamous epithelia and squamous cell carcinoma
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.
Authors
- Benjamin H. Jenkins (ORCID: https://orcid.org/0000-0002-7588-0044)
- Sunwoo Oh (ORCID: https://orcid.org/0000-0001-9205-4660)
- Emma V. King (ORCID: https://orcid.org/0000-0003-0658-1873)
- Mark Edmond (ORCID: https://orcid.org/0000-0002-6354-3526)
- Benjamin P. Sharpe (ORCID: https://orcid.org/0000-0002-7594-1601)
- Reuben S. Harris (ORCID: https://orcid.org/0000-0002-9034-9112)
- Tim R. Fenton (ORCID: https://orcid.org/0000-0002-4737-8233)
- Sangeetha Mahadevan (ORCID: https://orcid.org/0000-0002-6356-6509)
- Nur Syafinaz Zainal (ORCID: https://orcid.org/0009-0005-3799-6897)
- Rémi Buisson (ORCID: https://orcid.org/0000-0002-7196-8209)
- John Doorbar (ORCID: https://orcid.org/0000-0002-4027-102X)
- Ian Tracy (ORCID: https://orcid.org/0000-0003-4624-672X)
- Nagayasu Egawa
- Simak Ali (ORCID: https://orcid.org/0000-0002-1320-0816)
- Michael A. Carpenter (ORCID: https://orcid.org/0000-0001-9524-5323)
- Ian Reddin
- Christopher J. Hanley (ORCID: https://orcid.org/0000-0003-3816-7220)
- Damian Amendra (ORCID: https://orcid.org/0000-0002-7350-5144)
- Paige Policelli (ORCID: https://orcid.org/0000-0002-8854-0081)
- Ke Zheng (ORCID: https://orcid.org/0009-0009-1231-8941)
- Nicola Jane Smith (ORCID: https://orcid.org/0009-0004-9940-1070)
- Anjali Rao
- Gareth J. Thomas
- Emma Howes
Institutions
- Howard Hughes Medical Institute (US)
- The University of Texas at San Antonio Health Science Center (US)
- University of California, Irvine (US)
- University of Kent (GB)
- University of Cambridge (GB)
- Hammersmith Hospital (GB)
- AstraZeneca (Switzerland) (CH)
- Gilead Sciences (United States) (US)
- University of Southampton (GB)
- Imperial College London (GB)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2024-11-15
- DOI
- https://doi.org/10.1038/s44318-024-00298-9
- Citations
- 4
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 1.14
Funders
- AstraZeneca
- Cancer Prevention and Research Institute of Texas
- Cancer Research UK
- National Institute for Health and Care Research
- Rosetrees Trust
- Biotechnology and Biological Sciences Research Council
- National Cancer Institute