Discovery on gene x environment interactions may improve mesothelioma outcomes

November 24, 2021

Flavia Novelli, an Italian postdoctoral researcher in the laboratory of Michele Carbone, MD, PhD, and Haining Yang, MD, PhD, at the University of Hawaiʻi Cancer Center, is the first author of a paper published in the Proceedings of the National Academy of Sciences of the U.S. (PNAS). In this publication, Novelli and collaborators reported their discovery that BAP1, HMGB1, and the enzyme HDAC1 bind to each other to form a trimer, a macromolecular component, that lessens the risk of developing mesothelioma, a cancer of the lining of the lungs and abdomen.

Group photo of the Carbone and Yang laboratory members

“Our findings explain mechanistically the observed Gene x Environment interaction in mesothelioma that occurs in carriers of germline BAP1 mutations exposed to asbestos,” said Novelli.

“This publication is the result of amazing teamwork and collaboration between many incredible international scientists. The outcome is a meaningful research paper that we hope will help prevent cancer and improve many people’s lives.”

For many years, researchers at the UH Cancer Center have been at the forefront of mesothelioma research. Carbone and Yang discovered that mutations of the gene called BAP1 cause mesothelioma and other cancers. BAP1 is a powerful tumor suppressor gene, which means that when this gene is inactivated by mutations, the risk of developing cancer significantly increases. In parallel studies, Carbone and Yang discovered that asbestos causes the extracellular release of HMGB1, a protein that promotes inflammation and mesothelioma.

Novelli’s discovery brings these two lines of research together. She found that when the levels of BAP1 are reduced due to mutations, the BAP1-HMGB1-HDAC1 trimer is disrupted and HMGB1, a nuclear protein, is released extracellularly, triggering cancer. This process is enhanced by exposure to asbestos, which also causes the release of HMGB1. Therefore, carriers of BAP1 mutations are very susceptible to asbestos carcinogenesis and mesothelioma.

Encouragingly, Novelli and collaborators found that reducing HMGB1 activity with aspirin or other chemicals in mice that carry BAP1 mutations and are exposed to asbestos significantly reduced the number of mice that developed mesothelioma.

Going forward, the researchers, in collaboration with Marcus Tius, PhD, MS, professor of chemistry at the University of Hawaiʻi, will search the Native Hawaiian natural products library to identify and synthesize small molecules that bind and block the activity of extracellular HMGB1 for clinical trials to prevent or decrease mesothelioma growth.