Loss of Dnmt3a and Dnmt3b does not affect epidermal homeostasis but promotes squamous transformation through PPAR-γ

Abstract

The DNA methyltransferase Dnmt3a suppresses tumorigenesis in models of leukemia and lung cancer. Conversely, deregulation of Dnmt3b is thought to generally promote tumorigenesis. However, the role of Dnmt3a and Dnmt3b in many types of cancer remains undefined. Here, we show that Dnmt3a and Dnmt3b are dispensable for homeostasis of the murine epidermis. However, loss of Dnmt3a-but not Dnmt3b-increases the number of carcinogen-induced squamous tumors, without affecting tumor progression. Only upon combined deletion of Dnmt3a and Dnmt3b, squamous carcinomas become more aggressive and metastatic. Mechanistically, Dnmt3a promotes the expression of epidermal differentiation genes by interacting with their enhancers and inhibits the expression of lipid metabolism genes, including PPAR-γ, by directly methylating their promoters. Importantly, inhibition of PPAR-γ partially prevents the increase in tumorigenesis upon deletion of Dnmt3a. Altogether, we demonstrate that Dnmt3a and Dnmt3b protect the epidermis from tumorigenesis and that squamous carcinomas are sensitive to inhibition of PPAR-γ.DOI: http://dx.doi.org/10.7554/eLife.21697.001

Loss of DNA methyltransferase activity in primed human ES cells triggers increased cell-cell variability and transcriptional repression

“…MEIS1/2, PBX1, HOXB1, SOX4) and 3AKO ectoderm (SOX11, SOX9, ZIC2, POU4F1, PAX7). DNMT3A is often mutated in human tumors (Kim et al, 2013), has been shown to act as a first hit mutation (Shlush et al, 2014), and its loss in hematopoietic stem cells and the epidermis promotes leukemia and squamous cell carcinoma formation, respectively (Rinaldi et al, 2017;Yang et al, 2016). It will be interesting in the future to further explore the possible role of increased transcriptional variability in tumor initiation and progression.…”

DNA Methylation in Epidermal Differentiation, Aging, and Cancer

“…On the one hand, depletion of DNMT3A and DNMT3B was observed to impair human EpSC self-renewal and, in the case of DNMT3A, also affect differentiation in experiments performed both in vitro and with reconstituted epithelia in nude mice (Rinaldi et al, 2016). On the other hand, conditional deletion of Dnmt3a, Dnmt3b, or both in the epidermis of adult mice did not produce any obvious defect (Rinaldi et al, 2017). Mechanistically, de novo DNMTs have been found to associate with and promote the activity of enhancers controlling key genes for EpSC self-renewal and differentiation (Rinaldi et al, 2016).…”

Targeting cancer stem cell pathways for cancer therapy

“…391,392 However, combined expression of Dnmt3a and Dnmt3b inhibits PPARγ expression by direct methylation of its promoter in squamous carcinomas. 393 PPARs are also closely related to the metabolism of CSCs. PPARα and PPARβ/δ regulate metabolic reprogramming in glioblastoma stem cells, lung CSCs, and mouse mammary gland cancer.…”