Differentiation signals induce APOBEC3A expression via GRHL3 in squamous epithelia and squamous cell carcinoma
Differentiation signals induce APOBEC3A expression via GRHL3 in squamous epithelia and squamous cell carcinoma
Two APOBEC (apolipoprotein-B mRNA editing enzyme catalytic polypeptide-like) DNA cytosine deaminase enzymes (APOBEC3A and APOBEC3B) generate somatic mutations in cancer, 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, we show that in squamous cell carcinoma tissues, there is expansion of GRHL3 expression and activity to a subset of cells undergoing DNA replication and concomitant extension of APOBEC3A expression to proliferating cells. These findings indicate a mechanism for acquisition of APOBEC3A mutagenic activity in tumours.
Smith, Nicola
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Reddin, Ian
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Policelli, Paige
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Oh, Sunwoo
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Buisson, Rémi
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Zainal, Nur
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Howes, Emma
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Jenkins, Benjamin
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Tracy, Ian
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Sharpe, Benjamin
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Amendra, Damian
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Hanley, Christopher
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King, Emma
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Thomas, Gareth
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Edmond, Mark
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Ali, Simak
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Zheng, Ke
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Egawa, Nagayasu
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Doorbar, John
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Carpenter, Michael
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Harris, Reuben
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Rao, Anjali
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Mahadevan, Sangeetha
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Fenton, Tim
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4 March 2024
Smith, Nicola
a0865888-7864-485c-865a-698fd111dc7a
Reddin, Ian
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Policelli, Paige
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Oh, Sunwoo
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Buisson, Rémi
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Zainal, Nur
4ea20c88-b706-4815-8269-f9fd9b71f4ea
Howes, Emma
8ade564a-cf47-4eb1-ac79-40f9737d41e9
Jenkins, Benjamin
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Tracy, Ian
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Sharpe, Benjamin
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Amendra, Damian
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Hanley, Christopher
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King, Emma
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Thomas, Gareth
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Edmond, Mark
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Ali, Simak
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Zheng, Ke
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Egawa, Nagayasu
a75157f7-dc73-4696-a762-8a92da39d77f
Doorbar, John
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Carpenter, Michael
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Harris, Reuben
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Rao, Anjali
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Mahadevan, Sangeetha
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Fenton, Tim
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