EZH2 and Polycomb Repression in Cancer

How PRC2 Silences Genes

PRC2 catalyses mono-, di- and tri-methylation of H3K27. The tri-methyl mark (H3K27me3) is a hallmark of stably repressed chromatin and is read by other polycomb complexes that further compact the region. During development, PRC2 keeps lineage-inappropriate genes off.

EZH2 also has functions beyond H3K27 methylation, including methylation of non-histone proteins and PRC2-independent roles, which complicates simple models of what an EZH2 alteration does.

Gain-of-Function Contexts

In follicular lymphoma and a subset of diffuse large B-cell lymphoma, recurrent point mutations at EZH2 Y646 and nearby residues increase H3K27me3 and lock B cells in a proliferative germinal-centre-like state. High EZH2 expression without mutation is also seen in many solid tumours.

The EZH2 inhibitor tazemetostat is approved for EZH2-mutant relapsed or refractory follicular lymphoma and for epithelioid sarcoma, where the mechanism is different.

Loss-of-Function and Synthetic Lethality

In myeloid malignancies and T-cell acute lymphoblastic leukaemia, EZH2 inactivating mutations occur, marking it as a tumour suppressor in that setting. Separately, tumours that have lost the SWI/SNF subunit SMARCB1, such as epithelioid sarcoma and rhabdoid tumours, become dependent on residual EZH2 activity, which is the rationale for using an EZH2 inhibitor there.

So the same drug class is used both against an EZH2 gain-of-function mutation and against a SWI/SNF loss that creates EZH2 dependence.

Testing and Practical Use

Using an EZH2 inhibitor in lymphoma depends on a validated EZH2 mutation test, since benefit is concentrated in mutant tumours, whereas the epithelioid-sarcoma indication is defined by loss of SMARCB1 (INI1) staining rather than an EZH2 result. The two indications need different companion assays.

Tazemetostat is generally well tolerated, with fatigue, nausea and cytopenias the common effects and a small long-term risk of secondary lymphoma noted in early studies. Its modest single-agent activity in EZH2-wild-type disease is why combinations are the main direction of further work.

Key Takeaways

• ·EZH2 is the enzyme that writes the repressive H3K27me3 mark as part of PRC2.
• ·It is an oncogene in germinal-centre lymphomas and a tumour suppressor in some myeloid cancers.
• ·EZH2 inhibitors are approved for EZH2-mutant follicular lymphoma and for SMARCB1-deficient epithelioid sarcoma.