A new editorial paper was published in Oncotarget's Volume 14 on February 11, 2023, entitled, “Unveiling the Non-Canonical Functions of EZH2 in Prostate Cancer.” Prostate cancer (PCa) is ranked as the second leading cause of cancer-related death among American men, excluding skin cancer. In this new editorial, researchers Yang Yi, Yanqiang Li, Kaifu Chen, and Qi Cao from Northwestern University’s Feinberg School of Medicine discuss a well-known oncogenic driver in PCa: enhancer of zeste homolog 2 (EZH2)--canonically known for the functions as the catalytic subunit of polycomb repressive complex 2 (PRC2) that deposes histone H3 lysine 27 mono, di-, and tri-methylation (H3K27me1-3) and represses transcription. “Although the oncogenic role of EZH2 mainly relies on its enzymatic activity and the PRC2, accumulating evidence suggests that targeting the lysine methyltransferase activity of EZH2 alone is ineffective in treating EZH2-dependent malignancies including PCa.”