Liver cancer cells may rely on their own cholesterol-making machinery to survive and grow, researchers at Duke University School of Medicine have found.
The team, led by G. Greg Wang, PhD, discovered that the cancer-associated protein EZH2 partners with a master regulator of cholesterol production to drive tumor growth, revealing an unexpected vulnerability that could be exploited therapeutically.
The findings challenge the conventional view of EZH2 as primarily a gene-silencing protein.
EZH2 is overexpressed in many cancers, including liver cancer, but scientists have not fully understood how it promotes tumor growth. In the new study, published in Nature Cell Biology, the team mapped EZH2's activity across the genomes of liver cancer cells. The work revealed it plays an unexpected role: partnering with a protein called SREBP2 to activate genes that help cells make cholesterol.
“It is a surprise to see that EZH2 non-canonically interacts with SREBP2 to sustain cholesterol biosynthesis in cancer, pointing to a multifunctional role of EZH2 in orchestrating tumor epigenetic and metabolic states,” Wang said.
The researchers further showed that experimental protein-degrading drugs known as PROTACs, which destroy specific proteins rather than simply blocking them, reduced levels of both EZH2 and SREBP2. In preclinical models, disrupting this pathway suppressed cholesterol-producing genes and slowed tumor growth.
The work identifies what the researchers describe as a previously unrecognized vulnerability in liver cancer and suggests new opportunities to target tumors that depend on EZH2-driven cholesterol production.
Wang said his lab will next further optimize PROTACs that target EZH2 into drug-like candidates and test the most promising ones in preclinical liver cancer models, either alone or in combination with current anti-tumor drugs.
Other Duke authors: Arum Kim, Bo Pan, Chenxi Xu, Haiqing Zhong, Ling Cai.
Funding: The National Institutes of Health (National Cancer Institute), the Duke Cancer Institute Cancer Center Support Grant (National Cancer Institute).