Epitranscriptomic research opens the door to novel cancer drug targets - The RNA methyltransferase METTL6 as a potential oncogene

Cancer is a very short word for a large and diverse family of diseases and for the impact it has on the people affected, their families and friends as well as health care systems. Cancer is one of the biggest scientific, medical and societal challenges. The development of novel anti-cancer treatments, in particular with the potential for personalised treatment has therefore the highest priority. Recently, Dr. Valentina Ignatova and Prof. Robert Schneider from the Institute of Functional Epigenetics at the Helmholtz Zentrum München reported promising findings that can advance epitranscriptomics to fight cancer. The scientific adventure they started took them well beyond cancer…

METTL 6 regulates tumor cell growth.@EpigeneticsHMGU

Smoking, wrong diet, obesity, unhealthy lifestyle, radiation, physical inactivity, infections, heredity… are all considered potential causes for cancer. The list of causes is almost as long as the list of cancer types. More than 200 different cancer types are known in human and they all have something in common: abnormal cells that can multiply without any control and spread into different body parts. Most often these cells arise from a single cell or a handful of cells, where things ‘have gone wrong’. But what causes the initial error in a cell that leads to the development of a cancer cell? Classically, these initial errors are mutations in the genetic material the DNA, our hard drive. Our hereditary information is stored in more than 20 thousand gens in our genome. The DNA sequence of genes can be written into an RNA and then translated into a protein, which is the functional output of this gene. Therefore, mutations in the DNA often affect the proteins that make our cells work.

However, in the last years it became clear that cancer causing alterations can occur on different levels: not only genetically, but also epigenetically* and/or epitranscriptomically** and are also often linked to an alerted metabolism. While genetic mutations have a direct effect on the DNA sequence, epigenetic or epitranscriptomic alterations do not affect the DNA sequence directly. In a normal cell, these mechanisms ensure that only the proteins required for the cellular function and identity are produced. In a cancer cells, however, these mechanisms can be dysregulated. 

In their recent publication in Science Advances, the team of researchers led by Dr. Valentina Ignatova and Prof. Robert Schneider from the Institute of Functional Epigenetics shared their findings about the RNA-modifying enzyme Mettl6 that could serve as a drug target in cancer therapy. “We are working in the rather novel research field “Epitranscriptomics” that focusses on RNA modifications, such as RNA methylation,” explained Dr. Ignatova. “In the last few years, it has become increasingly clear that RNA modification pathways can be misregulated in many human cancers.” Thus, the team screened 78 different RNA-methyltransferases for their tumorigenic potential and found that METTL6 promotes tumour cell growth. “Interestingly, when we analysed data derived from liver cancer patients, we could observe that patients with low METTL6 levels had increased survival rates suggesting that it could be a potential drug target,” said Prof. Schneider. “Because nothing was known about METTL6, we decided to have a closer look into its activity and its mechanisms of action.” In doing so, they could identify that METTL6 methylates so-called transfer-RNAs (tRNAs), which transport amino acids to the protein synthesis machineries. Reducing METTL6 levels in cells resulted in altered protein synthesis and affects the differentiation potential of stem cells. “The next step was to study the function of METTL6 in the context of a full organism to reveal its physiological relevance: Thus, we generated mice deficient of METTL6 in collaboration with the German Mouse Clinic and the Institute of Experimental Genetics,” said Dr. Ignatova. “We found that our mice exhibited a reduced metabolic rate.” Prof. Schneider added: “What is quite remarkable – this puts us into a great position to study how epitranscriptomic mechanisms can contribute to metabolic health and cancer. We continue to work hard towards this angle for the near future.”

Altogether, the researchers identified the RNA methyltransferase METTL6 as a new oncogene that promotes tumour cell growth and regulates metabolic homeostasis. “METTL6 could be a potential therapeutic target for anti-proliferative cancer drugs, but also to help us understand the links between cancer and metabolic dysfunction, “anticipates Prof. Schneider. “Thus, we will now start to screen for selective and potent small molecules inhibitors for METTL6 to advance discovery of epitranscriptomic drugs.”

To read the full article, please go here.

Further Information:

* Epigenetics: Epigenetics refers to many different processes that are involved in changing gene expression without changing the DNA sequence of the gene. Within the nucleus, our genome is packaged into a structure called chromatin that consist of DNA and proteins. The nucleus functions like a suitcase during travelling that stores the most valuable things insides, including clothes, laptop, books and so on. However, that it fits into the suitcase, all stuff has to be packaged properly. Similar, to this the DNA needs to be packaged into chromatin to fit into the tiny nucleus. However, many biological processes require access to the DNA. Thus, it is essential that the DNA can be unpacked. If we go to the beach, we also would like to have our swimsuit from the suitcase with us. And this is where epigenetic processes come to action. They can open up the chromatin structure at a specific region of the DNA, if needed, but they can also close this region again.

** Epitrancriptomics: The transcriptome refers to all the RNAs that are produced by transcription within a cell. Similar to Epigenetics, Epitranscriptomics refers to the processes that include biochemical modifications of an RNA without changing its sequence and such RNA modifications can also impact gene expression.