The latest paper of Professor Fan Hong’s team entitled “DNA methyltransferase 3A isoform b contributes to repressing E-cadherin through cooperation of DNA methylation and H3K27/H3K9 methylation in EMT-related metastasis of gastric cancer” is published in Oncogene on May 2, 2018. This study provides a novel epigenetic mechanism underlying the metastatic gastric cancer (GC).
GC is one of the most common fatal malignancies worldwide. Aberrant DNA methylation is recognized as one of the most frequent events in cancer metastasis. DNA methylation provides a stable repression mark that modulates the expression of tumor-related genes and is mediated by a family of enzymes called DNA methyltransferases (DNMTs). In recent years, DNMT3A was identified as a key molecular involved in epigenetic regulation, which interact with histone methyltransferase and noncoding RNA to affect the expression of tumor-related genes. Notably, the aberrant regulation of DNMT3A is implicated in multiple types of cancers, especially haematological malignancies. However, its clinical significance and detailed functional role in solid tumours is unknown, although abnormal expression has gained widespread attention in these cancers.
In this study, we show a novel function and molecular mechanism of DNMT3A short isoform b (DNMT3Ab) in metastatic GC. We utilized clinical samples, in vitro and in vivo functional studies, and genome-wide identification showing that the causal relationship between DNMT3Ab and GC progression. DNMT3Ab could promote GC cells migration, invasion and metastasis by increasing cell motility and inducing epithelial-mesenchymal transition (EMT). Its aberrant expression indicates an independent prognostic indicator in patients with GC. Mechanistic studies further indicate that DNMT3Ab mediates the epigenetic inaction of the E-cadherin gene via DNA hypermethylation and histone modifications of H3K9me2 and H3K27me3. Depletion of DNMT3Ab effectively restores the expression of E-cadherin and reverses TGF-β-induced EMT by reducing DNA methylation, H3K9me2 and H3K27me3 levels at the E-cadherin promoter. Importantly, DNMT3Ab cooperated with H3K9me2 and H3K27me3 contributes to the transcriptional regulation of E-cadherin in a Snail-dependent manner. These results represent a significant step forward in understanding the contribution of DNMT3A and its isoforms to GC metastasis and in providing a potential target for epigenetic-based GC therapy.
This paper is completed by the first author Cui he and all members of the laboratory, which is guided by professor Fan Hong, the director of the Department of genetic and development biology. In addition, this work is supplied by the grants from National Natural Science Foundation of China. Currently, Professor Fan Hong’s team have published several papers in Oncogene, which provide a systematic research about the progression of GC and liver cancer .
