Scientists from the LMU (Ludwig-Maximilians-UniversitÃ¤t), from Munich, Germany reveal a new target for cancer therapy. Their study reveals that a protein, known as c-MYC, is responsible for regulating hundreds of different genes. Some of those regulated genes are also involved in cell growth and proliferation. Any genetic changes that cause the perturbation of the protein’s activity will have a major impact of the homeostasis of the tissue, most often leading to cancer. Precedent studies have already shown that in the majority of cancer cases there is a hyperactivation of the c-MYC gene. Moreover, the c-MYC protein plays a key role in metastasis, through the stimulation of EMT (epithelial-mesenchymal transition). Thus, high levels of the c-MYC protein is responsible for inducing the metastasis of tumors.
Professor Heiko Hermeking, one of the main authors of the study, reports that through the use of a colorectal cancer model, the research team has managed to study the interactions of the ZNF281 protein with the c-MYC protein. Due to the fact that there was scarce information about the ZNF281 control mechanisms, Hermeking’s research team focused on investigating the regulatory segment of the ZNF281 gene. Their findings revealed that the ZNF281 gene is actually the hub of a very complex network that is involved in metastasis.
Researchers say that the ZNF281 is responsible for the activation of the SNAIL (also known as SNAI1 or the Drosophila embryonic protein). This creates a positive feedback loop that further increases the expression of the ZNF281 gene. However, at the same time, the ZNF281 gene also interacts with other genes that activate the epithelial-mesenchymal transition. This fact makes the interaction with SNAI1 only be a part of the metastasis process.
The study shows that the ZNF281 expression is normally limited through the action of miR-34a. In turn, the transcription of miRNA-34a is inhibited by SNAI1. Thus, the SNAI1 gene is responsible for increasing the levels of ZNF281. In Hermeking’s precedent studies, he discovered that p53 (a tumor suppressor) is responsible for the onset of the miR-34a transcription. The interaction between p53 and miR-34a is considered to be part of a protective mechanism that stops EMT, thus preventing metastasis.
SNAI1 is responsible for the promotion of metastasis through two different mechanisms. The first mechanism refers to the activation of the mRNA that encodes ZND281, subsequently provoking the second mechanism – the inhibition of the miRNA-34a expression. This type of two-pronged mechanism is also known as feed-forward regulation.
In conclusion, the research team managed to confirm that ZNF281 is directly involved in cancer metastasis by examining its effects on mouse models. Hermeking concluded that the inhibition of the ZNF281 gene is able to prevent metastasis, at least in mouse models. Therefore, it is possible that the inhibition of the ZNF281 gene could lead to the inhibition of the metastasis process in human subjects as well. Hermeking and his team hope that in their future studies they will be able to develop new anti-cancerous therapeutics that could be able to stop metastasis as well.