Your skin's natural cancer defense is compromised by sunlight, which deactivates it. A recent study in Nature Communications reveals how prolonged UV radiation exposure triggers inflammatory reactions in skin cells by degrading a crucial protein called YTHDF2. This protein acts as a guardian, preventing normal skin cells from turning cancerous. The research highlights YTHDF2's central role in RNA metabolism regulation, offering new insights into skin cancer prevention and treatment strategies.
UV Radiation, Inflammation, and Rising Skin Cancer Cases
Skin cancer is a prevalent concern, with nearly 5.4 million Americans diagnosed annually, and over 90% of these cases linked to excessive UV exposure. UV radiation can damage DNA and induce oxidative stress in skin cells, triggering inflammation that causes sunburn symptoms like redness, pain, and blisters.
Yu-Ying He, PhD, a Professor of Medicine at the University of Chicago, explains their interest in understanding how UV-induced inflammation contributes to skin cancer development.
RNA, or ribonucleic acid, is vital for translating genetic information into proteins. Non-coding RNAs, a group of RNA molecules, regulate gene activity without producing proteins. These non-coding RNAs function in the nucleus or cytoplasm, influencing cellular processes.
How YTHDF2 Protects Skin Cells
He's lab focuses on environmental stressors like UV radiation and arsenic in drinking water, which disrupt molecular pathways and promote cancer. Experiments revealed that UV exposure significantly reduces YTHDF2 levels in cells. YTHDF2 is an RNA-binding protein that recognizes RNA sequences tagged with N6-methyladenosine (m6A).
Removing YTHDF2 from skin cells exacerbated UV-triggered inflammation, indicating its role in suppressing inflammatory responses.
Inflammation, while essential for infection defense, can drive serious diseases if uncontrolled. The molecular mechanisms regulating this response after UV damage are still unclear.
Non-Coding RNA, Immune Sensors, and UV Stress
The researchers used multi-omics approaches and cell-based tests to show that YTHDF2 binds to U6, a non-coding RNA with m6A modification, categorized as small nuclear RNA (snRNA). Under UV stress, cancer cells accumulated U6 snRNA, which interacted with toll-like receptor 3 (TLR3), an immune sensor triggering inflammatory pathways associated with cancer.
Surprisingly, these interactions occurred inside endosomes, cellular compartments typically involved in material recycling, not U6 snRNA hosting.
He explained their efforts to understand how non-coding RNAs reach the endosome, as it's not their usual location. They discovered that SDT2, a protein, transports U6 into the endosome, accompanied by YTHDF2.
A Cellular Surveillance System Against Excessive Inflammation
Once YTHDF2 and m6A-modified U6 RNA reach the endosome, YTHDF2 prevents TLR3 activation. Without YTHDF2, U6 RNA binds TLR3 freely, triggering harmful inflammatory responses.
He emphasized the study's revelation of a biological regulation layer, a surveillance system through YTHDF2, protecting the body from excessive inflammation and damage.
This pathway suggests potential strategies for preventing or treating UV-induced skin cancer by targeting RNA-protein interactions controlling 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.
