UF research team discovers new role of RBM33 in head and neck cancer cell growth

A University of Florida research team has discovered a new role of a key protein in driving changes in the genetic material of cells, which has the potential to contribute to the development of cancer. The findings could pave the pay for new therapeutic targets for head and neck cancers.

Zhijian Qian, Ph.D.

“We found that two proteins play an important role in tumor growth in head and neck cancer by forming a complex with each other and regulating RNA m6A demethylation,” said Zhijian Qian, Ph.D., a professor and Pierre Chagnon Professor of Cancer Research in the division of hematology and oncology in the UF College of Medicine. “We further demonstrated that suppressing either protein could significantly inhibit head and neck cancer cell growth in vitro and in vivo in mice, indicating that the proteins could be therapeutic targets for these cancers.”

Qian, a member of the UF Health Cancer Center’s Mechanisms of Oncogenesis research program, is the lead author of the study, published on May 30 in the journal Molecular Cell.

Head and neck cancers usually begin in the cells that line the surfaces of the head and neck, such as those inside the mouth, throat and voice box.

Inside cells, mRNA is like an owner manual, ferrying instructions on how proteins are made. But mRNA can veer off script through dynamic processes called mRNA methylation, in which small molecules called methyl groups are added or removed from RNA. This modification primarily occurs on the nitrogenous base adenine, leading to the formation of N6-mehtyladenosine, or m6A. RNA binding proteins play a vital role in these processes, which influence genetic expression. Dysregulation of these processes has been associated with a variety of human diseases, including cancer.  

In the new study, the team set out to determine how one unstudied RNA binding protein, RBM33, works in mRNA methylation, which is one of the most prevalent and dynamic modification identified in mRNA. The biological function of about one-third of all RNA binding proteins remains unknown, and little was previously known about how RMB33 worked in cancer.

The researchers found that RBM33 plays a critical role in the mRNA demethylation process by forming a complex with m6A demethylase ALKBH5. The team further uncovered the mechanism by which RBM33 regulates a key gene involved in head and neck cancer cell growth.

“By forming this complex, the proteins work together to target specific areas of RNA for m6A demethylation and play a crucial role in cancer growth,” Qian said. “This finding is a major step forward in understanding how the process of mRNA demethylation works because the substrate selectivity of ALKBH5 demethylase remains unknown. If we can target the interaction between these two proteins, we can efficiently and selectively inhibit tumor cell growth.”

To reach their conclusions, the team used various cell types, as well as samples of primary head and neck cancer tumors from patients. The study builds on the group’s prior work assessing mRNA methylation in leukemia. Further studies are needed to determine whether the new complex could have a role in other types of cancer, Qian said.

The study’s first author is Fang Yu, Ph.D., a postdoctoral researcher who was recently promoted to be a research assistant professor in Qian’s lab. Co-first authors include collaborators from the laboratory of Chuan He, Ph.D., a well-known scientist in the field of RNA biology from the University of Chicago.

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