PQQ Inhibits PRC2 Methyltransferase Activity and Suppresses the Proliferation of B‐Cell Lymphoma In Vitro

Polycomb repressive complex 2 (PRC2) is a multi-subunit complex that catalyzes the tri-methylation of histone H3 at lysine 27 (H3K27me3), serving as an epigenetic marker of gene silencing. PRC2 plays a crucial role in numerous fundamental biological processes, and its dysregulation is closely linked to cancer and developmental disorders. EZH2, a key component of PRC2, is aberrantly overexpressed in various human cancers. Inhibition of EZH2 enzymatic activity has been shown to effectively reduce cancer cell proliferation and tumorigenesis. Consequently, EZH2 is widely recognized as a driver of cancer, and the development of EZH2-specific inhibitors has become an active area of research. In this study, we screened over 2000 compounds from solid libraries using a PRC2 enzymatic activity assay and identified pyrroloquinoline quinone (PQQ) as a potent inhibitor of PRC2 methyltransferase activity in vitro. We evaluated the antitumor effects of PQQ across different tumor cell lines and found that it exhibited strong anticancer activity, specifically against B-cell lymphoma cells, which demonstrate elevated EZH2 activity. We used a combination of biochemical assays, cellular assays, and molecular docking studies to thoroughly investigate the inhibitory effects of PQQ on PRC2 activity. Furthermore, PQQ is a naturally occurring compound with various biological activities, including antioxidant and neuroprotective effects, and it has been approved as a nutritional supplement and health product in the United States. This study demonstrates, for the first time, that PQQ, a dietary supplement, selectively inhibits PRC2 methyltransferase activity, therefore providing new insights for targeted anti-lymphoma therapies involving PRC2.