Enhancer of Zeste Homolog 2, or EZH2, refers to both a gene and the protein it produces. This protein serves as a master regulator within our cells, functioning like a switch operator for the vast network of genes that make up our genetic blueprint. Its fundamental purpose involves turning specific genes “on” or “off” to control cellular processes. This precise regulatory function is foundational for maintaining normal cell activity throughout the body.
The Biological Role of EZH2
The normal operation of EZH2 is deeply intertwined with epigenetics, a field exploring modifications that influence gene activity without altering the underlying DNA sequence. EZH2 is a core component of a larger protein assembly known as the Polycomb Repressive Complex 2 (PRC2). Within this complex, EZH2 acts as the primary enzyme, specifically a histone methyltransferase.
It adds methyl groups, small chemical tags, to specific sites on histone proteins. EZH2 primarily targets lysine 27 on histone H3, creating H3K27me3. This tagging compacts DNA, silencing genes in that region. This gene silencing is significant during embryonic development and cell differentiation, ensuring specialized cells maintain their identity.
EZH2’s Connection to Disease
When EZH2’s normal function goes awry, it can significantly contribute to the development and progression of various diseases, primarily cancers. Two main scenarios describe how EZH2 drives pathology: overexpression and specific mutations. Overexpression occurs when the body produces too much EZH2 protein, leading to an excessive and inappropriate silencing of genes.
Many genes improperly silenced by EZH2 overexpression are tumor suppressor genes, which normally brake uncontrolled cell growth. With these genes silenced, cells divide uncontrollably, promoting cancer. Specific “gain-of-function” mutations, such as at amino acid Y641, can also occur in the EZH2 gene. These mutations create a hyperactive EZH2 protein, more efficient at silencing genes and enhancing tumor suppressor repression. This dysregulation of EZH2 is commonly implicated in various cancers, including follicular lymphoma, diffuse large B-cell lymphoma, prostate cancer, breast cancer, melanoma, and epithelioid sarcoma.
Targeting EZH2 with Inhibitors
Understanding how EZH2 contributes to disease has led to the development of targeted therapies known as EZH2 inhibitors. These drugs are designed to directly interfere with the enzymatic activity of the EZH2 protein. The mechanism of action involves these molecules fitting into the active site of the EZH2 enzyme.
By occupying this site, EZH2 inhibitors block the enzyme from adding methyl groups to histone H3. This inhibition prevents the abnormal gene silencing that drives cancer progression. Consequently, previously silenced tumor suppressor genes can be reactivated, restoring the cell’s natural ability to control growth and undergo programmed cell death (apoptosis).
Approved Treatments and Clinical Use
The scientific understanding of EZH2’s role has translated into tangible treatments for patients. Tazemetostat, known by the brand name Tazverik, is an FDA-approved EZH2 inhibitor. This oral medication is approved for adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete surgical removal.
It is also approved for adult patients with relapsed or refractory follicular lymphoma. For follicular lymphoma, it is used when tumors are positive for an EZH2 mutation (e.g., at codons Y646, A682, or A692) and the patient has received at least two prior systemic therapies. It is also approved for follicular lymphoma patients without other satisfactory alternative treatment options. Ongoing research continues to explore the potential expansion of EZH2 inhibitors for use in other cancer types, including diffuse large B-cell lymphoma, prostate cancer, and mesothelioma.