Table 1.

Post-Translational Modifications of EZH2

Modification	Site	Modifier	Function	Reference
Phosphorylation	S21	AKT	Suppresses EZH2 HMT activity by impeding affinity of EZH2 for nucleosome substrate Promotes the noncanonical methylation of STAT3 and STAT3 activity in GBM cells Appears to be required for androgen-independent growth of castration-resistant prostate cancer cells Appears to be required for the transcriptional activation activity of EZH2 in CRPC	4,11,12
Phosphorylation	Y244	JAK3	Promotes dissociation of PRC2 members; Increases noncanonicalEZH2 interaction with RNA PolII, promotes proliferation of NK/T-cell lymphoma cells	13
Phosphorylation	T261	CDK5-related protein	Promotes degradation by F-box and WD repeat domain-containing 7	14
Phosphorylation	T311	AMP kinase	Disrupts interaction between EZH2 and SUZ12, resulting in reduced canonical H3K27 trimethylation Associated with better survival in breast and ovarian cancer patients	15
Phosphorylation	T345	CDK1, CDK2, PKCg	Promotes degradation; cell-cycle dependent, increases binding to HOTAIR ncRNA and 5′ end of Xist Promotes recruitment of EZH2 to target gene loci and maintenance of H3K27me3 levels at these target loci in prostate cells	16, 17, 18
Phosphorylation	S363	GSK3β	Not yet known	19
Phosphorylation	T367	p38α GSK3β	Promotes satellite cell differentiation in response to TNFα through PJA1-mediated degradation of EZH2 Induces cytoplasmic localization of EZH2 and binding to vinculin and other cytoskeletal regulators of cell migration and invasion; critical for TNBC metastasis Contributes to histologic diversity and behavior of metaplastic breast tumors Reduces H3K27me3 activity and reduces migratory/invasive properties in MCF12A and MDA-MB-231 overexpressing cells	19, 20, 21, 22
Phosphorylation	T416	CDK2	Enhances migration, invasion, stemness in TNBC cells Serves as a docking site for the forkhead-associated domain of NIPP1, which prevents dephosphorylation and is required for EZH2 association with proliferation loci	23,24
Phosphorylation	T487	CDK1 PKCg	Promotes ubiquitination and degradation by the proteasome; negatively regulates proliferation in PC3 prostate cancer cells Disrupts binding with SUZ12 and EED, thereby suppressing H3K27 methyltransferase activity Promotes differentiation of mesenchymal stem cells	25, 26, 27
Phosphorylation	Y641	JAK2	Promotes B-TrCP (FBXW1)-mediated degradation	28
Phosphorylation	S652	ATM	May negatively regulate interaction with PRC2 members SUZ12 and EED and negatively regulate stability	29
Phosphorylation	S690	PKCg	Not yet known	27
Phosphorylation	S734	ATM	May negatively regulate interaction with PRC2 members SUZ12 and EED and negatively regulate stability	29
O-GlcNacylation	S75	OGT	Likely positively regulates EZH2 protein stability	30
Acetylation	K348	PCAF and SIRT1 (deacetylation)	Decreases phosphorylation at T345 and T487, increases EZH2 stability, may affect H3K27me3-mediated repression of EZH2 target genes May enhance transcriptional silencing of HOXA10 in lung carcinoma cells; may enhance lung cancer cell migration and invasion	31
Methylation	K307	SMYD2	Dimethylation at K307 critical for EZH2 protein stability, protecting from ubiquitination and degradation and thereby contributing to breast cancer cell invasion	32
Methylation	R432	PRMT1	Asymmetric demethylation which inhibits CDK-1 mediated phosphorylation of EZH2 at T345 and T487, thereby preventing ubiquitination by TRAF6 Contributes to breast cancer cell invasion and metastasis	33
Methylation	K510	PRC2 (auto)	Increases activity, promotes accessibility to H3 tail	34,35
Methylation	K514	PRC2 (auto)	Increases activity, promotes accessibility to H3 tail Significantly reduced in diffuse intrinsic pontine glioma cells carrying H3K27M mutation	34,35
Methylation	K515	PRC2 (auto)	Not known	34,35
Ubiquitination	K421	SMURF2	Proteasomal degradation	36,37
Ubiquitination		Praja1, FBXW, FBXW7, TRAF6	Protein instability and degradation	14,20,33,38, 39, 40
PARylation	D233, E239	PARP1	Loss of PARylation results in PRC2 dissociation, EZH2 down-regulation, and decreased H3K27me3	41

Shown are the demonstrated post-translational modifications of EZH2 occurring across multiple systems.

GBM, glioblastoma multiforme.