Your skin has a built-in cancer defense and sunlight turns it off

In a new study in Nature Communications, scientists at the University of Chicago report how long-term exposure to ultraviolet (UV) radiation can set off inflammatory reactions in skin cells by breaking down a key protein called YTHDF2. This protein acts like a gatekeeper that helps stop normal skin cells from turning cancerous. The researchers showed that YTHDF2 is central to controlling RNA metabolism so that cells remain healthy, and their work points to possible new strategies for preventing and treating skin cancer.

UV Radiation, Inflammation, and Rising Skin Cancer Cases

Every year, almost 5.4 million people in the United States receive a skin cancer diagnosis, and more than 90% of these cases are linked to excessive UV exposure. UV radiation can injure DNA and generate oxidative stress in skin cells, which in turn triggers inflammation that causes the familiar redness, pain, and blistering of sunburn.

"We're interested in understanding how inflammation caused by UV exposure contributes to the development of skin cancer," said Yu-Ying He, PhD, Professor of Medicine in the Section of Dermatology at the University of Chicago.

RNA, or ribonucleic acid, is a crucial molecule that helps translate genetic information into proteins. One important group of RNA molecules, known as non-coding RNAs, regulates gene activity without making proteins. These non-coding RNAs usually carry out their functions either in the nucleus, where the cell's DNA is located, or in the cytoplasm, where most cellular processes occur.

How YTHDF2 Helps Protect Skin Cells

He's laboratory focuses on how environmental stressors, including UV radiation and arsenic in drinking water, disrupt molecular pathways and damage cellular systems in ways that promote cancer. In their experiments, the team screened multiple enzymes and discovered that UV exposure significantly lowers the amount of YTHDF2 in cells. YTHDF2 is a "reader" protein that specifically recognizes RNA sequences tagged with a chemical modification called N6-methyladenosine (m6A).

"When we removed YTHDF2 from skin cells, we saw that UV-triggered inflammation was much worse," He said. "This suggests that the YTHDF2 protein plays a key role in suppressing inflammatory responses."

Inflammation is vital for defending the body against infections, but if it is not carefully controlled, it can drive serious diseases, including cancer. The detailed molecular mechanisms that keep this response in check after UV damage, however, are still not fully understood.

Non-Coding RNA, Immune Sensors, and UV Stress

Using multi-omics approaches and additional cell-based tests, the researchers showed that YTHDF2 binds to a particular non-coding RNA called U6, which carries an m6A modification and is categorized as a small nuclear RNA (snRNA). Under UV stress, cancer cells accumulated higher levels of U6 snRNA, and these modified RNAs were found to interact with toll-like receptor 3 (TLR3), an immune sensor known to trigger inflammatory pathways associated with cancer.

Unexpectedly, these interactions took place inside structures called endosomes, cellular compartments that usually help recycle materials rather than host U6 snRNA.

"We spent a lot of time figuring out how these non-coding RNAs get to the endosome, since that's not where they usually reside," He explained. "For the first time, we showed that a protein called SDT2 transports U6 into the endosome, and YTHDF2 travels with it."

A Cellular Surveillance System Against Excessive Inflammation

Once YTHDF2 and m6A-modified U6 RNA reach the endosome, YTHDF2 prevents the RNA from activating TLR3. When YTHDF2 is missing, such as after UV-induced damage, U6 RNA can bind freely to TLR3 and set off harmful inflammatory responses.

"Our study uncovers a new layer of biological regulation, a surveillance system through YTHDF2 that helps protect the body from excessive inflammation and inflammatory damage," He said.

This newly described pathway suggests potential strategies for preventing or treating UV-induced skin cancer by targeting the interactions between RNA and proteins that control inflammation.

The study, "YTHDF2 regulates self non-coding RNA metabolism to control inflammation and tumorigenesis," was supported by grants from the National Institutes of Health, the University of Chicago Medicine Comprehensive Cancer Center, the ChicAgo Center for Health and EnvironmenT (CACHET), and the University of Chicago Friends of Dermatology Endowment Fund.

Additional authors include Seungwon Yang, Yan-Hong Cui, Haixia Li, Jiangbo Wei, Gayoung Park, Ming Sun, Michelle Verghese, Emma Wilkinson, Teresa Nam, Linnea Louise Lungstrom, Xiaolong Cui, Tae Young Ryu, Jing Chen, Marc Bissonnette, and Chuan He from the University of Chicago