Author Response: Loss of Dnmt3a and Dnmt3b Does Not Affect Epidermal Homeostasis but Promotes Squamous Transformation Through PPAR-γ
March 2017
TLDR Loss of Dnmt3a and Dnmt3b leads to more aggressive skin tumors, but blocking PPAR-γ can reduce this effect.
The study explored the role of Dnmt3a and Dnmt3b in skin carcinogenesis, revealing that their loss did not impact epidermal homeostasis but promoted squamous transformation via PPAR-γ. Loss of Dnmt3a in keratinocytes increased tumorigenesis post-DMBA treatment, with Dnmt3a-cKO mice developing more tumors with high PPAR-γ expression, suggesting PPAR-γ inhibition as a potential therapy. The study noted a slight increase in mutations, particularly Cytosine to Thymine, in Dnmt3a-cKO tumors, possibly due to impaired TDG glycosylase activity. It concluded that Dnmt3a affects tumor initiation rather than progression, as more tumors were initiated without increased H-RAS or N-RAS mutations. Despite these findings, Dnmt3a and Dnmt3b were not crucial for epidermal differentiation or homeostasis, indicating the complexity of DNA methylation in gene regulation and tumorigenesis, warranting further research.
