Professor Dan Levy, a researcher at Ben-Gurion University in the Negev and the Negev National Institute of Biotechnology (NIBN), has discovered a new mechanism that is a promising target for cancer therapy.
“Our perception of the specific multi-step molecular mechanical process that regulates the initiation and progression of the cancer found in this study may allow us to develop new therapeutic strategies to optimize cancer treatment. While we have studied this mechanism in models of breast cancer, we are currently extending it to other types of cancer such as melanoma and glioblastoma, ”explains Professor Levy.
The results were published in Scientists progress.
“Our understanding of the progression and treatment of human cancer depends in large part on our ability to scientifically explore and decipher in depth the various cellular events that control these processes. A central process that regulates cancer pathology is gene expression, or in other words, what are the mechanisms that turn a gene on or off? Can we control selective gene expression to achieve a delicate balance in cancer-related cellular processes? Can we direct specific cellular factors to regulate this process? Obtaining such a balance will allow the cell to decide which genes to activate in a given time and which tissue will subsequently determine whether a cell will become malignant or not, ”explains Professor Levy.
This process is partly maintained by post-translational modifications. One of these modifications is methylation, which refers to the addition of a chemical moiety (a methyl group) to a lysine residue in a given protein.
In this article, the collaborating research teams identified and characterized a novel methylation event, catalyzed by the methyltransferase SETD6, on the transcription factor BRD4. BRD4 has a fundamental role in the regulation of gene expression and has thus become a promising epigenetic therapeutic candidate for targeting various pathologies. In a complete biochemical, molecular and genomic study, they provided evidence that methylation of BRD4 inhibits the expression of genes involved in translation and abolishes protein synthesis in cells. Methylation of BRD4 determines the recruitment of the E2F1 transcription factor to selected target genes that are involved in the generation of proteins, a molecular mechanism that facilitates the balanced expression of these genes. Imbalanced gene expression involved in protein synthesis can lead to increased proliferation and transformation which can subsequently lead to cancer initiation and progression.
Professor Levy is a member of the Department of Microbiology, Immunology and Genetics of Shraga Segal of the Faculty of Health Sciences as well as the National Institute of Biotechnology of the Negev (NIBN). The research was led by Dr Zlata Vershinin, post-doctoral fellow in Professor Levy’s laboratory, within the framework of an exceptional scientific collaboration with the research group of Dr Rab Prinjha (pharmaceutical company Glaxo smith Kline); Prof. Mark Dawson (University of Melbourne); Panagis Filippakopoulos (University of Oxford) and Dr Barak Rotblat and Dr Vered Caspi from Ben Gurion University.
The research was funded by the Israel Science Foundation (ISF), the Research Career Development Award from the Israel Cancer Research Fund and the Israel Cancer Association.
Prof. Levy’s lab is focused on studying additional protein methylation pathways such as cell cycles, programmed cell death, DNA damage control, DNA repair, adipocyte differentiation, etc. “These pathways and others have a direct effect on the development of diseases such as different types of cancer and metabolic diseases such as diabetes, fatty liver disease, obesity, etc.”, explains Professor Levy.
“Our research has great potential for the identification of new therapeutic targets. Indeed, our research group is concerned with the development of specific molecules to modulate the enzymatic and cellular activity of SETD6 and other methyltransferases. Such agents could be used in the future for the generation of therapeutic strategies ”, explains Professor Levy.