Enhancer of zeste homolog 2 (EZH2) and Differentiation antagonizing non-protein coding RNA (DANCR) complex (EZH2-DANCR)

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), which mediates the trimethylation of histone H3 at lysine 27 (H3K27me3) to promote gene silencing (UniProt P35226; PubMed 24367506). Differentiation Antagonizing Non-Protein Coding RNA (DANCR) is a long non-coding RNA (lncRNA) that plays a pivotal role in maintaining cell stemness and is frequently overexpressed in various malignancies (HGNC 28876; PubMed 32733114). The EZH2-DANCR complex represents a functional interaction where DANCR acts as a molecular scaffold or guide, recruiting EZH2 to the promoters of specific target genes, such as tumor suppressors like SOCS3 or p21 (PubMed 31863615; PubMed 29152559). This recruitment leads to the epigenetic repression of these genes, thereby promoting oncogenic processes including increased cell proliferation, epithelial-mesenchymal transition (EMT), and metastasis (PubMed 30034155; PubMed 27248174). Pharmacological targeting of this axis primarily involves EZH2 inhibitors such as Tazemetostat, which are approved for treating epithelioid sarcoma and follicular lymphoma by disrupting the enzymatic activity of the complex (PubMed 32581322). Research is also exploring the potential of RNA-targeted therapies, such as antisense oligonucleotides, to specifically disrupt the DANCR-EZH2 interaction as a more precise therapeutic strategy for DANCR-dependent cancers (PubMed 32733114).

Other names

EZH2-DANCR axisEZH2-DANCR interactionDANCR-EZH2 complexANCR-EZH2Differentiation antagonizing non-protein coding RNA-Enhancer of zeste homolog 2 interaction

Inhibition of the EZH2 methyltransferase activity within the PRC2 complex, which prevents the DANCR-mediated recruitment of EZH2 to target promoters and the subsequent H3K27me3-mediated silencing of tumor suppressor genes (PubMed 31863615; PubMed 29152559).