Damage to these ‘protective mechanisms’ can promote the development of lung cancer

GRAND RAPIDS, Michigan (June 22, 2023) — Loss of two key “protective” proteins initiates epigenetic changes that turn healthy lung cells into cancer cells, according to new research from Van Andel Institute scientists.

The findings, published in Cancer researchis the first to demonstrate a completely epigenetic origin of cancer cells and may have implications for future cancer treatment and prevention strategies.

“Our findings shed light on the importance of epigenetics in cancer development,” said Gerd Pfeifer, Ph.D., a VAI professor and senior study author. “In theory, it is easier to target epigenetics than genetics in cancer treatment, which opens up new possibilities for the development of therapies.”

Most cancers arise from mutations in DNA sequences, which interfere with the genetic instructions necessary for normal function. The resulting errors allow malignant cells to develop and spread, crowding out healthy cells and causing disease.

However, since the 1980s, scientists have recognized the role of another important regulatory system in cancer development: epigenetics.

Epigenetic mechanisms regulate whether a gene is “on” or “off” by adding or removing chemical tags called methyl groups. Improper methylation wreaks havoc by activating or silencing genes at the wrong times; for example, genes that regulate cell death may be mistakenly switched off, allowing cancer cells to replicate uncontrollably.

Although epigenetic mechanisms are now recognized as central players in cancer, exactly how these processes work remains unclear.

To find the answer, Pfeifer and colleagues focused on two proteins that protect more than 4,000 genes from improper methylation: TET and RYBP.

Their study, conducted in a laboratory model of lung cancer, revealed that loss of TET or RYBP by itself had minimal to moderate impact. Loss of both, however, leads to widespread aberrant methylation — and, by extension, cancer.

Their findings suggest that the combination of RYBP and TET is essential for maintaining normal function. RYBP helps maintain the massive protein complex called PRC1, which protects thousands of genes from methylation. The TET protein protects the genome by removing methylation if it doesn’t conform. When these protective mechanisms are damaged together, methylation spirals out of control.

Going forward, Pfeifer plans to explore this process in other types of cancer to investigate whether it is a phenomenon confined to lung cells or whether it has broader applications. If the combined loss of RYBP and TET in other cell types has the same result, it could have far-reaching implications for our understanding of cancer and the development of new therapies.

Authors include Wei Cui, Ph.D., Zhijun Huang, Ph.D., Seung-Gi Jin, Ph.D., Jennifer Johnson, MS, Kin H. Lau, Ph.D., and Galen Hostetter, MD, of VAI. owned by VAI Genomic Core, Core Pathology and Biorepository, Optical Imaging Core And Livestock Core also contributed to this work.

The research reported in this publication was supported by the Van Andel Institute and the National Cancer Institute of the National Institutes of Health under award no. R01CA234595 (Pfeifer). Its contents are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health.

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The Van Andel Institute (VAI) is committed to improving health and improving the lives of present and future generations through cutting-edge biomedical research and innovative educational offerings. Founded in Grand Rapids, Michigan, in 1996 by the Van Andel family, VAI is now home to more than 500 scientists, educators and support staff, who work with a growing number of national and international collaborators to drive discovery. Institute scientists study the origins of cancer, Parkinson’s and other diseases and translate their findings into breakthrough prevention and treatment strategies. Our educators are developing an inquiry-based approach to K-12 education to help students and teachers prepare the next generation of problem solvers, while our Graduate School offers Ph.D. program in molecular and cellular biology. Learn more at vai.org.