Sunlight holds a vital place in supporting human well-being by enabling the production of crucial substances like vitamin D within the body. However, prolonged time under the sun’s rays dramatically elevates the risk of skin cancer development.
UV Radiation, Inflammation, and the Surge in Skin Cancer Diagnoses
A recent investigation published in Nature Communications by researchers from the University of Chicago reveals that extended exposure to ultraviolet (UV) radiation initiates inflammatory processes in skin cells through the degradation of a critical protein known as YTHDF2. This protein serves as a protective barrier, preventing ordinary skin cells from transforming into cancerous ones. The study demonstrates that YTHDF2 plays a pivotal role in managing RNA metabolism to maintain cellular health, opening doors to innovative approaches for skin cancer prevention and therapy.
Annually, approximately 5.4 million individuals in the United States are diagnosed with skin cancer, with over 90% of these instances attributed to overexposure to UV light. UV radiation damages DNA and induces oxidative stress in skin cells, sparking inflammation that leads to the characteristic symptoms of sunburn, including redness, discomfort, and blisters.
“Our research delves into the ways UV-induced inflammation contributes to skin cancer progression,” explained Yu-Ying He, PhD, a Professor of Medicine in the Dermatology Section at the University of Chicago.
RNA, or ribonucleic acid, functions as an essential intermediary that converts genetic instructions into functional proteins. A significant category of RNA molecules, referred to as non-coding RNAs, influences gene expression without producing proteins themselves. These molecules typically perform their roles either in the nucleus, the home of the cell’s DNA, or in the cytoplasm, the site of most cellular activities.
The Protective Role of YTHDF2 in Skin Cells
The laboratory led by He examines how environmental factors, such as UV radiation and contaminants like arsenic in water supplies, interfere with molecular pathways and impair cellular functions, ultimately fostering cancer growth. Through their experimental screenings of various enzymes, the team found that UV exposure substantially reduces YTHDF2 levels in cells. YTHDF2 is classified as a reader protein that identifies specific RNA sequences marked with an N6-methyladenosine (m6A) chemical modification.
“Removing YTHDF2 from skin cells intensified UV-triggered inflammation significantly,” He noted. “This indicates that YTHDF2 is essential for dampening inflammatory reactions.”
While inflammation is crucial for combating infections and safeguarding the body, uncontrolled inflammation can propel the onset of severe conditions, including cancer. The precise molecular processes that regulate this response following UV injury remain incompletely mapped out.
Non-Coding RNAs, Immune Detection, and Responses to UV Stress
Employing advanced multi-omics techniques alongside cell-based assays, the scientists determined that YTHDF2 attaches to a specific non-coding RNA named U6, which bears an m6A modification and belongs to the small nuclear RNA (snRNA) family. In the presence of UV stress, cancer cells exhibited elevated accumulation of U6 snRNA, and these altered RNAs interacted with toll-like receptor 3 (TLR3), an immune sensor that activates inflammation-linked pathways implicated in cancer development.
Surprisingly, these interactions occurred within endosomes, which are intracellular compartments typically involved in material recycling rather than housing U6 snRNA.
“We invested considerable effort in unraveling how these non-coding RNAs end up in the endosome, as it’s an atypical location for them,” He elaborated. “We have demonstrated for the first time that a protein termed SDT2 shuttles U6 into the endosome, with YTHDF2 accompanying it.”
A Built-In Cellular Monitoring System to Curb Overactive Inflammation
Upon arriving in the endosome, YTHDF2 alongside the m6A-modified U6 RNA inhibits the RNA from stimulating TLR3. In the absence of YTHDF2, as occurs post-UV damage, U6 RNA binds unbound to TLR3, igniting detrimental inflammatory cascades.
“This research reveals a novel regulatory mechanism-a vigilant surveillance system mediated by YTHDF2 that shields the body from runaway inflammation and associated harm,” He stated.
The pathway identified in this study offers promising avenues for interventions aimed at preventing or managing UV-related skin cancer by modulating the RNA-protein interactions that govern inflammation.
The publication, titled “YTHDF2 regulates self non-coding RNA metabolism to control inflammation and tumorigenesis,” received funding 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.
Contributing authors from the University of Chicago 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.
