Northwestern Medicine scientists have discovered that an enzyme called EZH2 can activate expression of the androgen receptor gene, which drives prostate cancer growth. The function is distinct from the enzyme’s already well-established role in silencing tumor-suppressor genes.
The findings led the scientists to further demonstrate that a new strategy of simultaneously blocking both functions of EZH2 suppressed prostate cancer progression in both cell and animal models.
The study, published in Cell Reports, was led by Jindan Yu, MD, PhD, professor of Medicine in the Division of Hematology and Oncology and of Biochemistry and Molecular Genetics.
Jung Kim, PhD, an alumna of the Driskill Graduate Program in Life Sciences (DGP), and Yongik Lee, PhD, a postdoctoral fellow, were co-first authors of the paper.
EZH2 has long been an important research focus of the Yu laboratory. The enzyme is the catalytic subunit of a group of proteins called Polycomb Repressive Complex 2, and catalyzes methylation of a histone called H3 at its lysine 27 — a modification which leads to epigenetic silencing of target genes.
Yu has previously published extensively on EZH2’s ability to turn off tumor-suppressor genes, a mechanism that promotes prostate cancer growth. EZH2 is highly expressed in aggressive forms of prostate cancer, and cancer cells without the EZH2 gene cannot survive.
However, inhibitors that block the catalytic function of EZH2 have so far failed to improve outcomes in prostate cancer.
“That led us to hypothesize that there must be an important function of EZH2 that is not dependent on its catalytic function,” said Yu, also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
In the current study, the scientists discovered that beyond EZH2’s well-known function in turning genes off, the enzyme can also turn on genes, an important one of which is the androgen receptor.
“Our study is paradigm-shifting because we show that EZH2 can actually work as an activator,” Yu said. “And this function is both independent of its methylation function and separate from its Polycomb Repressive Complex.”
The novel findings help explain why prostate cancer cells may have been insensitive to the epigenetic inhibitors, which only blocked one function of the enzyme.
The team of scientists thus suggested a new therapeutic approach: “We thought in order to fully inhibit EZH2, you need to block both its epigenetic function and its ability to turn on the androgen receptor,” Yu said.
The scientists tested combining an EZH2 inhibitor with enzalutatmide, an androgen receptor antagonist, and found that the drug combination significantly curbed cancer progression in models of prostate cancer.
The Yu laboratory is now working to better understand the mechanisms underlying EZH2’s function as a gene activator. In August, Yu received a National Institutes of Health RO1 grant to investigate how a co-activator called NF90 might mediate EZH2’s role in gene activation, as well as further explore simultaneously blocking the two roles of EZH2 as a treatment approach in advanced prostate cancer.
The study was supported in part by NIH R01CA172384, P50CA180995 and R50CA211271; American Cancer Society Research Scholar Award RSG-12-085-01; Department of Defense W81XWH-17-1-0405; and an institutional Ruth L. Kirschstein National Research Service award from the National Institute of Diabetes and Digestive and Kidney Diseases (T32 DK007169).
