News Release

PHILADELPHIA – Mutations of the gene MLL4 in epithelial skin cells can inhibit healthy cell turnover and may lead to keratinocyte cancers, which collectively outnumber all other human cancers. Targeting pathways altered by MLL4 mutations to induce proper cell turnover and death offers an approach to suppress tumor growth, according to a new study from the Perelman School of Medicine at the University of Pennsylvania. The study was published this month in the journal Science Advances.

The gene MLL4 is one of the most commonly mutated genes across all of human cancers. Previous work has shown that MLL4 is linked to tumor suppression in a variety of cancers, but its role in skin cancer was unknown. In order to uncover how MLL4 influences cancer growth, researchers knocked out only this gene in the epithelial tissues of mice and found that skin cells proliferated, the skin thickened, and a form of normal skin cell turnover and death, called ferroptosis, was inhibited.

“Your skin cells need to be able to undergo cell death,” said Brian Capell, MD, PhD, an assistant professor of Dermatology and Genetics and lead author of the study. “If cells don’t die and turn over, they stick around, continue to grow, and become cancerous. We saw that a loss of MLL4 impaired ferroptosis by activating genes that encourage tumor growth while simultaneously suppressing genes that prevent cancerous proliferation.”

To combat cancer-cell development in individuals with MLL4 genetic mutations, the researchers believe that specific medications that can promote ferroptosis may be a future way to inhibit cancer growth and encourage healthy cell turnover.

“The good news is that there are pharmaceuticals currently available that correct and promote the pathways that are impaired when MLL4 is mutated,” said Capell. “Our lab plans on studying whether these ferroptosis-promoting medications can be effective to treat skin cancers like squamous cell carcinoma. Another potential avenue for treatment involves testing whether these medications can be given in combination with other anti-cancer drugs such as immunotherapies to enhance the abilities of each to stop cancers.”

Aside from cancer, the Penn scientists believe that modulating ferroptosis may have a significant impact on other skin disorders marked by aberrant skin turnover, too, such as psoriasis. According to the American Academy of Dermatology Association, it’s estimated that over 85 million Americans have some kind of skin disease.

The research was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases grants (K08AR070289, R01AR077615, T32AR007465, and 5K08AR075846), the Damon Runyon Cancer Research Foundation, and the Dermatology Foundation.


Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, excellence in patient care, and community service. The organization consists of the University of Pennsylvania Health System and Penn’s Raymond and Ruth Perelman School of Medicine, founded in 1765 as the nation’s first medical school.

The Perelman School of Medicine is consistently among the nation's top recipients of funding from the National Institutes of Health, with $550 million awarded in the 2022 fiscal year. Home to a proud history of “firsts” in medicine, Penn Medicine teams have pioneered discoveries and innovations that have shaped modern medicine, including recent breakthroughs such as CAR T cell therapy for cancer and the mRNA technology used in COVID-19 vaccines.

The University of Pennsylvania Health System’s patient care facilities stretch from the Susquehanna River in Pennsylvania to the New Jersey shore. These include the Hospital of the University of Pennsylvania, Penn Presbyterian Medical Center, Chester County Hospital, Lancaster General Health, Penn Medicine Princeton Health, and Pennsylvania Hospital—the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is an $11.1 billion enterprise powered by more than 49,000 talented faculty and staff.

Share This Page: