Differentiation signals induce APOBEC3A expression via GRHL3 in squamous epithelia and squamous cell carcinoma
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View abstract on PubMed
Summary
This summary is machine-generated.APOBEC3A and APOBEC3B enzymes cause mutations in cancer. In normal cells, these enzymes aren't active during DNA replication, but in tumors, APOBEC3A becomes active in replicating cells, driving cancer mutations.
Area Of Science
- Genetics
- Molecular Biology
- Cancer Research
Background
- APOBEC3A and APOBEC3B are DNA cytosine deaminases that introduce somatic mutations in cancer, contributing to tumor development and drug resistance.
- Understanding the expression patterns and regulation of these enzymes is crucial for deciphering their role in mutagenesis.
Approach
- Utilized single-cell RNA sequencing to analyze APOBEC3A and APOBEC3B expression in healthy and malignant mucosal epithelia.
- Validated findings using immunohistochemistry, spatial transcriptomics, and functional experiments.
- Investigated the role of Grainyhead-like transcription factor 3 (GRHL3) in regulating APOBEC3A expression.
Key Points
- In normal tissues, APOBEC3B is expressed in mitotic keratinocytes, while APOBEC3A is mainly in terminally differentiating cells, requiring GRHL3.
- Neither enzyme is highly expressed during DNA replication in normal cells, the stage linked to APOBEC-mediated mutagenesis.
- In squamous cell carcinoma, GRHL3 expands to replicating cells, leading to APOBEC3A expression in proliferating tumor cells.
Conclusions
- The study reveals distinct expression patterns for APOBEC3A and APOBEC3B in normal and cancerous mucosal epithelia.
- Identified a mechanism where GRHL3-mediated expansion of APOBEC3A expression to replicating cells in tumors contributes to mutagenic activity.
- These findings provide insights into how APOBEC3A acquires mutagenic potential in cancer.
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