METTL1: A new cancer target?

New research provides strong evidence that targeting METTL1 can curb certain cancers, while leaving other cells in the body untouched. (Images: AdobeStock/Illustration: Sebastian Stankiewicz, Boston Children’s Hospital)

A protein that modifies RNAs called METTL1 could be a target for treating some aggressive, difficult-to-treat cancers, new research in Molecular Cell suggests. The study provides evidence that blocking METTL1 inhibits the ability of cancer cells to grow, killing them selectively, and the researchers believe it can be addressed with drugs.

METTL1 and related proteins had previously been found at higher concentrations in certain cancer cells, including some brain, blood, pancreatic and skin cancers. The new study examines data from The Cancer Genome Atlas and confirms that expression of the METTL1 gene is enhanced in several cancers, including glioblastoma and sarcoma, and is associated with poor survival. It also shows that the copy number amplification of the METTL1 gene leads to excessive amounts of METTL1 protein. This, in turn, causes previously normal cells to replicate faster and transform into a malignant state, producing highly aggressive tumors.

“This research sheds some light on the role of the METTL1 protein in cancer development and proves that its overproduction can cause a cell to become cancerous,” said Richard Gregory, PhD, of the Stem Cell Research Program at Boston Children’s Hospital. and the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. Gregory led the study with Konstantinos Tzelepis, PhD, of the University of Cambridge in collaboration with the Wellcome Sanger Institute.

Blocking Malignant Transformation

METTL1 belongs to a family of RNA-modifying proteins involved in cell replication. The RNA modification increases the translation and production of growth-promoting, oncogenic proteins, the researchers showed.

When they genetically inhibited the production of METTL1 — using a short hairpin RNA to knock down the METTL1 gene or CRISPR editing to delete it — they stopped the growth of cancer cells in lab and mouse models while targeting non-cancerous cells. left unharmed. When they did the opposite – overexpressing the METTL1 gene – they saw increased cell proliferation, accelerated cell cycle progression, enhanced colony formation and, in mice, increased tumor formation.

“Cancer cells take advantage of an unregulated cell cycle, which leads to increased replication,” says Gregory. “The more we understand about the genetic basis of cancer and how we can fight it, the more life-changing targeted treatments we can create.”

A medicinal target?

The researchers now hope to develop a small-molecule drug that would block METTL1, without the need for genetic engineering. A small molecule inhibitor for a similar protein, METTL3, has been developed to help treat acute myeloid leukemia and is expected to enter clinical trials in 2022. a wide range of aggressive cancers with high levels of METTL1 protein.

“Our research provides strong evidence that targeting METTL1 is an effective treatment against certain cancers, helping to kill cancer cells while leaving other cells in the body untouched,” said Esteban Orellana, PhD, lead author of the paper and a researcher. Pew and Damon Runyon Fellow of the Cancer Foundation at the Gregory Lab. “This could mean that there are fewer unpleasant side effects. The next step is to see if our encouraging results can be translated to the clinic.”

Learn more about research at Dana-Farber/Boston Children’s.

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