Cancer EZH2 is an attractive target for anti-cancer therapy because it helps cancerous cells divide and proliferate. It is found in larger amounts than in healthy cells in a wide range of cancers including breast, prostate, bladder,
uterine, and
renal cancers, as well as
melanoma and
lymphoma. EZH2 is a
gene suppressor, so when it becomes overexpressed, many tumor suppressor genes that are normally turned on, are turned off. Inhibition of EZH2 function shrinks
malignant tumors in some reported cases because those tumor suppressor genes are not silenced by EZH2. EZH2 typically is not expressed in healthy adults; it is only found in actively dividing cells, like those active during fetal development. Because of this characteristic, overexpression of EZH2 can be used as a diagnostic marker of cancer and some neurodegenerative disorders. Another important characteristic of EZH2 is that when EZH2 is overexpressed, it can activate genes without forming
PRC2. This is an issue because it means the methylation activity of the enzyme is not mediated by complex formation. In breast cancer cells, EZH2 activates genes that promote cell proliferation and survival. Importantly, the mutation of tyrosine 641 in the active SET domain to a number of different amino acids is a common feature of some B-cell lymphomas.
Inhibitors Developing an inhibitor of EZH2 and preventing unwanted histone methylation of tumor suppressor genes is a viable area of cancer research. EZH2 inhibitor development has focused on targeting the
SET domain active site of the protein. Several inhibitors of EZH2 have been developed as of 2015, including
3-deazaneplanocin A (DZNep), EPZ005687, EI1, GSK126, and UNC1999. ;DZNep: DZNep has potential antiviral and anti-cancer properties because it lowers EZH2 levels and induces
apoptosis in breast and colon cancer cells. In 2020,
tazemetostat, with the tradename Tazverik, gained an FDA
accelerated approval for the treatment of metastatic or locally advanced epithelioid sarcoma and an
accelerated approval for the treatment of patients with relapsed follicular lymphoma later that year. ;Sinefungin: Sinefungin is another SAM-competitive inhibitor, however, like DZNep, it is not specific to EZH2. indicating that EZH2 inhibition may not be beneficial in all cases.
Skeletal development EZH2 is crucial for epigenetic regulation of specific patterning during osteochondrogenesis, or bone and cartilage development, of the craniofacial skeletal elements. By repressing inhibitors, EZH2 promotes bone and cartilage formation in facial skeletal features arising from the neural crest. Above average EZH2 expression has become a biological marker for the most aggressive form for
breast cancer known as
Inflammatory Breast Cancer (IBC). But in 2013, a study performed by Zhaomei Mu and his associates concluded that the knockdown gene for EZH2 inhibited both the migration and invasion of IBC cells. Also
in vivo, its knockdown gene suppressed tumor growth, most likely by the presence of fewer blood vessels, or reduced angiogenesis, in the EZH2 knockdown tumor versus EZH2 tumors.
Weaver Syndrome Mutations in the EZH2 gene have been linked with
Weaver syndrome, a rare disorder characterized by advanced bone age,
macrocephaly, and
hypertelorism. The
histidine residue in the active site of the
wild-type EZH2 was mutated to
tyrosine in patients diagnosed with Weaver syndrome. The mutation likely interferes with
cofactor binding and causes disruption of the natural function of the protein. == Taxonomic distribution ==