EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)

While H3K27M mutations are hallmark features of diffuse midline gliomas, rare cases of posterior fossa ependymomas harboring these mutations have been reported. Recent studies suggest molecular similarities between diffuse midline gliomas and posterior fossa ependymomas expressing H3K27M and EZHIP, potentially reflecting shared hindbrain developmental programs in their biological origins.

Our lead ASO successfully corrects aberrant splicing and NMD, restores the expression and function of EZH2, and partially rescues hematopoietic defects and cellular properties. Our study demonstrates that ASO pharmacology is an actionable strategy for clinical development, challenging the existing paradigms in SF-mutated cancers.

In vitro assays demonstrated that PBs upregulated ESR1 and EZH2, induced DNA damage in normal breast epithelial cells, and enhanced proliferation and migration in breast cancer cells-effects reversed by ESR1 and EZH2 inhibitors. Together, these findings suggest that PBs may affect pathways relevant to breast cancer progression and act as potential environmental contributors.

The anti-tumor activity of NCTD is associated with the downregulation of EZH2 protein expression and concomitant inhibition of the JAK2/STAT3 signaling pathway. These findings provide novel insights into the molecular mechanisms underlying NCTD's anti-tumor activity.

Treatment with second-generation androgen receptor (AR) inhibitors, such as enzalutamide, can trigger lineage plasticity, promoting the transdifferentiation of PCa cells into an AR-independent, poorly differentiated neuroendocrine phenotype (NEPC)...Conclusions. These findings establish HOC as a multifaceted therapeutic entity capable of disrupting key NEPC oncogenic networks, highlighting its potential as a novel lead intervention for aggressive NEPC.

In vivo, xenograft assays in NOD-SCID mice reveal that while phosphorylated Lamin A/C or EZH2 promote tumor growth and metastasis, phospho-deficient mutants markedly suppress it. Lamin A/C-EZH2 interaction regulates the expression of E-M-associated transcription factors, highlighting the role of this interaction in modulating transcriptional plasticity, thereby serving as a potential therapeutic target for regulating metastasis in breast cancers.

Accordingly, EZH2 inhibitors cooperated with genetic or pharmacological inhibition of YAP/TEAD, which similarly induced BMF expression and apoptosis. Together, these findings show how EZH2 and YAP/TEAD coordinately insulate the BMF locus and demonstrate that EZH2 inhibitors can be used to reprogram HER2+ tumors, resulting in a dramatic sensitization to HER2 kinase inhibitors and enhanced killing of residual disease.

The study indicates that EZH2 can be a valuable predictive marker in HNC. Anti-EZH2 therapy should be explored to improve the treatment outcomes in patients with high expression of EZH2.

EZH2, p-STAT3, MYC, and p-ERK1/2 upregulation associate differently with disease progression depending on JAK2 mutation status. EZH2 and related signaling molecules could serve as potential therapeutic targets in myeloid neoplasms.

This study reveals a novel Decitabine-TRAF6-DNMT1-TRAF6-EZH2 regulatory axis in CRC. Decitabine has dual effects, suggesting a new therapy.

Therapeutic targeting of H3K27me3 with EZH2-selective inhibitors such as tazemetostat has shown clinical benefit in lymphoma; however, their efficacy is limited by functional redundancy with EZH1. The dual EZH1/2 inhibitor valemetostat overcomes this limitation by reactivating tumor suppressor genes, achieving durable responses in ATL and peripheral T-cell lymphoma (PTCL). Nonetheless, therapeutic resistance can emerge through PRC2 gatekeeper mutations and compensatory DNA methylation. These findings underscore the value of targeting the dysregulated epigenome and support the continued clinical development of dual EZH1/2 inhibitors.

Treatment with the dual EZH1/2 inhibitor UNC1999 and 5-azacytidine reactivated these PRC2 target genes, specifically in AML-HSPCs, toward normal gene expression patterns. These findings suggest that targeting Polycomb repression offers a promising epigenetic strategy for improving outcomes in KMT2A-rearranged AML.