Decision Letter: Loss of Dnmt3a and Dnmt3b Does Not Affect Epidermal Homeostasis but Promotes Squamous Transformation Through PPAR-γ
November 2016
Studysummary The research found that while Dnmt3a and Dnmt3b are not necessary for skin homeostasis in mice, the loss of Dnmt3a increases squamous tumor formation from carcinogens, and combined deletion of both results in more aggressive and metastatic tumors.
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The study explored the role of Dnmt3a and Dnmt3b in skin tumorigenesis, revealing that their loss did not impact normal epidermal homeostasis but facilitated squamous transformation via increased PPAR-γ expression. The absence of Dnmt3a in keratinocytes led to faster hair regrowth and increased tumorigenesis post-DMBA treatment, suggesting Dnmt3a's role in maintaining hair follicles in a dormant state. Although the study lacked functional data linking Dnmt to gene regulation in tumorigenesis, it found that inhibiting PPAR-γ delayed tumor appearance and reduced tumor numbers in Dnmt3a-cKO mice, indicating a potential therapeutic approach for skin squamous cell carcinomas. The research also noted a slight increase in Cytosine to Thymine mutations in Dnmt3a-cKO tumors, with no significant changes in genomic instability. Overall, the findings suggested that Dnmt3a and Dnmt3b were not essential for normal epidermal differentiation but played a significant role in tumor initiation through the PPAR-γ pathway.
