Table 1.

Regulation of EZH2 through PTMs and their functions

Type of PTMs	Condition	Modifying enzyme	Site	Biological Functions	Ref.
Phosphorylation	IGF-induced	AKT	S21	Decreases H3K27me3 level, releases EZH2 silenced target genes and promotes tumor development.	[31]
	Non-genomic ER signaling	AKT	S21	Reduces the activity of H3K27me3 and HMTase.	[77]
	Tat	AKT	S21	Decreases H3K27me3 level and increases EZH2 cytoplasmic translocation, activating HIV-1 transactivation.	[80,81]
	As3+	AKT	S21	Enhances Akt activation by upregulation of negative Akt regulator miR-21 via STAT3 S27 phosphorylation, contributing to pS21 EZH2 and oncogenesis.	[82,83]
	GSCs	AKT	S21	Promotes EZH2-mediated STAT3 methylation, enhances EZH2-STAT3 interaction and STAT3 activity	[84]
	-	CDK1 and CDK2	T350 in human	Enhances the silencing of target genes without affecting intrinsic HMTase activity or core PRC2 complex formation, promotes EZH2-mediated cell proliferation and migration.	[86]
	-	CDK1	T345 in Mouse	Increases Ezh2 interaction with HOTAIR and the 5’end of Xist, further mediating PRC2 recruitment to its target loci and tumor progression.	[87]
	-	CDK1	T492 in human (T487 in Mouse)	1. Inhibit HMTase activity, disrupt binding to other PRC2 components	[87,91,92]
				2. Promote ubiquitination and degradation by proteasome pathway
	-	CDK1	T487 in Human	Suppresses EZH2 HMTase activity and disassociates EZH2 from other PRC2 complex components, finally inhibiting cancer cell migration and invasion and promoting human mesenchymal stem cells differentiation into osteoblasts.	[91]
	MKK6 or TNFα	p38α Kinase	T372 in Mouse	Enhances interaction of YY1 and PRC2, represses Pax7 expression and impair satellite cell proliferation	[96]
Acetylation	-	PCAF	K348	Enhances EZH2 stability, promotes lung cancer cell migration and invasion	[32]
Ubiquitination	-	Smurf2	L421	Upregulates target gene PPARγ, essential for neuron differentiation of hMSCs and functional regeneration of CNS repair after ischaemic stroke	[33]
	Jak2-induced pY461 EZH2	β-TrCP	-	Reduces EZH2 protein stability and H3K27me3 activity	[110]
	YC-1, PKA and Src-Raf-1-MEK-ERK pathways	c-Cbl	T731 and T774	Leads to Src and ERK activation, resulting in formation of c-Cbl-ERK-EZH2 complex and enhancement of EZH2 uniquitination and degradation.	[111]
	DZNep treatment	PRAJA1	-	Ub-mediated proteasomal degradation of individual PRC2 subunits including EZH2, SUZ12 and EED	[112]
	FOXP3	PRAJA1	-	Facilitates EZH2 protein degradation through K48-linkage polyubiquitination and decreases cell proliferation, migration and formation in breast cancer cells	[113]
	-	ω-3 PUFAs	-	Decreases EZH2 expression and H3K27me3 level, upregulates EZH2 downstream target genes E-cadherin and IGFBP3, leading to suppression of tumor invasion and metastasis.	[114]
Sumoylation	-	-	-	EZH2 are sumoylated in vitro and vivo, but the biological functions remain unknown.	[34]
O-GlcNAcylation	OGT-dependent	-	S75	Maintains EZH2 protein stability H3K27me3 activity, eventually contributing to tumorigenesis	[35]