Loss of Dnmt3a and Dnmt3b does not affect epidermal homeostasis but promotes squamous transformation through PPAR-γ.
Loss of Dnmt3a and Dnmt3b does not affect epidermal homeostasis but promotes squamous transformation through PPAR-γ.
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DOI：
10.7554/elife.21697
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发表时间：
2017-04-20
期刊：
影响因子：
7.7
通讯作者：
Benitah SA
中科院分区：
文献类型：
--
作者：
Rinaldi L;Avgustinova A;Martín M;Datta D;Solanas G;Prats N;Benitah SA
DNA甲基转移酶Dnmt3a抑制白血病和肺癌模型的肿瘤发生。相反，Dnmt3b的放松被认为通常会促进肿瘤发生。然而，Dnmt3a和Dnmt3b在许多类型癌症中的作用仍未明确。在这里，我们发现Dnmt3a和Dnmt3b对于小鼠表皮的稳态是必不可少的。然而，dnmt3a（而非dnmt3b）的缺失会增加致癌物质诱导的鳞状肿瘤的数量，但不会影响肿瘤的进展。只有同时缺失Dnmt3a和Dnmt3b，鳞状癌才会变得更具侵袭性和转移性。在机制上，Dnmt3a通过与表皮分化基因的增强子相互作用来促进表皮分化基因的表达，并通过直接甲基化其启动子来抑制脂质代谢基因（包括PPAR-γ）的表达。重要的是，抑制PPAR-γ部分阻止了Dnmt3a缺失后肿瘤发生的增加。总之，我们证明Dnmt3a和Dnmt3b保护表皮免于肿瘤发生，并且鳞状癌对PPAR-γ的抑制敏感。DOI: http://dx.doi.org/10.7554/eLife.21697.001我们身体中的大多数细胞都含有相同的DNA。然而，我们的身体是由许多不同类型的细胞组成的，比如神经细胞或皮肤细胞，它们的功能非常不同。在每一种细胞类型中，只有特定的由DNA编码的基因是活跃的。被称为表观遗传调节因子的蛋白质负责产生不同的基因活动模式。如果表观遗传调节因子在错误的时间开启或关闭，它们可能会导致衰老和癌症等疾病。被称为DNA甲基转移酶的酶是一组表观遗传调节器。DNA甲基转移酶通过向DNA中添加小的化学基团甲基来控制基因的活性。其中两种酶——Dnmt3a和Dnmt3b——在细胞发育过程中起着重要作用，帮助细胞成熟并分化成不同的类型。缺乏这两种酶的小鼠要么在胚胎时期死亡，要么在出生后死亡。此外，这些酶在某些皮肤癌和各种其他人类癌症中发生突变或活性降低。在这里，Rinaldi等人研究了这些酶在成年小鼠中的作用。实验表明，在普通的实验室条件下，缺乏Dnmt3a和Dnmt3b的突变小鼠与正常小鼠一样健康。然而，当老鼠暴露在促进肿瘤生长的化学物质中，就像皮肤暴露在紫外线下一样，突变老鼠比正常老鼠产生了更多的皮肤肿瘤。此外，突变小鼠的肿瘤更容易在肺部形成继发性肿瘤。Rinaldi等人发现Dnmt3a减少了一种叫做PPAR-γ的蛋白质的产生，这种蛋白质有助于分解某些类型的脂肪分子。用一种抑制PPAR-γ活性的药物治疗突变小鼠，减缓了肿瘤的生长。总的来说，这些实验显示了DNA甲基转移酶在成年动物中起作用的新方式。未来的研究将调查抑制脂肪分解的药物是否有助于治疗Dnmt3a和Dnmt3b蛋白突变或活性降低的癌症。DOI: http://dx.doi.org/10.7554/eLife.21697.002
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 Most of the cells in our body contain the same DNA. However, our bodies are made of many different types of cell, such as nerve cells or skin cells, which perform very different jobs. In each cell type only certain sets of genes encoded by the DNA are active. Proteins known as epigenetic regulators are responsible for producing the different patterns of gene activity. If epigenetic regulators are switched on or off at the wrong time, they can contribute to ageing and diseases such as cancer. Enzymes known as DNA methyltransferases are one group of epigenetic regulators. DNA methyltransferases control the activity of genes by adding small chemical groups known as methyl groups to the DNA. Two of these enzymes – known as Dnmt3a and Dnmt3b – are important during development to help cells mature and specialize into different types. Mice that lack both of these enzymes either die as embryos or just after birth. Furthermore, these enzymes are mutated or less active in some skin cancers and various other human cancers. Here, Rinaldi et al. investigated the role these enzymes play in adult mice. The experiments show that under ordinary laboratory conditions, mutant mice that lacked Dnmt3a and Dnmt3b were as healthy as normal mice. However, when the mice were exposed to chemicals that promote tumor growth, which mimics skin exposure to UV light, the mutant mice developed many more skin tumors than the normal mice. Furthermore, the tumors in the mutant mice were more likely to form secondary tumors in the lung. Rinaldi et al. found that Dnmt3a reduced the production of a protein called PPAR-γ, which helps to break down some types of fat molecules. Treating the mutant mice with a drug that inhibits PPAR-γ activity slowed the growth of the tumors. Overall, these experiments show a new way in which DNA methyltransferases act in adult animals. Future research will investigate whether drugs that inhibit the breakdown of fats could help to treat cancers in which the Dnmt3a and Dnmt3b proteins are mutated or less active. DOI: http://dx.doi.org/10.7554/eLife.21697.002