Noncanonical association of EZH2 with E2F1 promotes tumor proliferation through chromatin remodeling.

Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the polycomb repressive complex 2 (PRC2), which mediates transcriptional repression through histone H3 lysine 27 trimethylation (H3K27me3), is highly expressed in aggressive triple-negative breast cancer (TNBC). However, despite the elevated EZH2 expression, H3K27me3 levels remain unexpectedly low, suggesting a potential noncanonical role for EZH2 in TNBC. Here we demonstrate that EZH2 directly binds to the transcription factor E2F1, and this interaction is critical for modulating chromatin accessibility by disrupting H3K27me3 deposition. This noncanonical function of EZH2, which operates independently of its methyltransferase activity, is linked to enhanced tumor cell proliferation and inhibition of apoptosis. Our findings reveal that EZH2 functions in a chromatin context-dependent manner by cooperating with E2F1 in TNBC, highlighting that the EZH2-E2F1 interaction, independent of PRC2, plays a key role in remodeling chromatin structure and facilitating TNBC proliferation.