By Lynn McCain

The Celina Kleer lab at the University of Michigan Department of Pathology and Rogel Cancer Center has found a new mechanism that fuels metastasis in triple negative breast cancers. In their new study they show that EZH2, a master regulator of cell type identity, known to function through methylation of histones, has a new, unexpected function in aggressive breast cancers. By adding methyl groups to the p38 protein, EZH2 enhances the ability of breast cancer cells to spread to other tissue throughout the body, a process known as metastasis.

“Our lab is dedicated to understand the mechanisms that breast cancer cells use to spread, so that more effective therapies can be developed and tested.” Celina Kleer, MD, professor of pathology and director of breast pathology, states.

The team’s findings appear in the journal iScience.

The work, funded by the National Cancer Institute, started years ago with Kleer’s observation under the microscope: EZH2, a protein known to function in the nucleus was present in the cytoplasm of triple negative breast cancer tissue samples. “This completely unexpected finding led us to an exciting journey of discovery in the lab. We were intrigued by the presence of EZH2 in the cytoplasm of cancer cells and how it may contribute to breast cancer progression,” Kleer explains.

“A major breakthrough in our studies is the identification of an EZH2-p38 reciprocal positive interaction that fuels cancer spread”, Kleer says. Talha Anwar, then a graduate student in the Kleer lab and now an internal medicine resident, initially showed that EZH2 relies on phosphorylation by the p38 protein to move into the cytoplasm. The team found that once in the cytoplasm, EZH2 methylates p38 prolonging its half-life and pro-invasive activity. With these exciting laboratory findings, the team was ready to test the significance of EZH2-p38 in metastasis.

Led by Maria Gonzalez, senior research specialist, they used specific drugs to inhibit EZH2 and p38 in mice with breast cancer. “We found that dual inhibition of EZH2 and p38 enzymatic activities reduces breast cancer progression in preclinical models, providing the basis for future studies testing the clinical and biomarker utility,” Maria Gonzalez states. “Pursuing this hypothesis has been extremely exciting. One of the most memorable moments was when we discovered that EZH2 indeed methylates p38, which delineates a new mechanism by which EZH2 increases TNBC metastasis, with potential therapeutic implications.”

“This work increases our understanding of how triple negative breast cancer cells spread based on the cooperation between EZH2 and p38 and may lead to more effective ways to block metastasis,” concluded Kleer.

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Paper cited: “EZH2 T367 phosphorylation activates p38 signaling through lysine methylation to promote breast cancer progression": 

iScience DOI:https://doi.org/10.1016/j.isci.2022.104827

Authors: Maria E. Gonzalez, Giuseppina Naimo, Talha Anwar, Alessandro Paoli, Shilpa Tekula, Suny Kim, Natasha Medhora, Shoshana Leflein, Jacob Itkin, Raymond Trievel, Kelley Kidwell, Yu-Chih Chen, Loredana Mauro, Euisik Yoon, Sebastiano Ando, and Celina G. Kleer

Funding: National Institutes of Health grants R01CA125577 and R01CA107469 (C.G.K.), F30CA19084 (T.A.), Department of Defense Breast Cancer Research Program grant W81XWH-19-1-0093 (C.G.K), and University of Michigan Rogel Cancer Center support grant P30CA046592 . C.G.K. is a Rogel Scholar. G.D.N. was supported by Italian Minister of University and Research ( MIUR , D.D. n. 407/2018)-PON R&I 2014–2020, A.P. was supported by MIUR Excellence Department Project funds (L.232/2016), Italy.