Merlin expression in Meso-17 and Meso-25 cells decreased FAK Tyr397 phosphorylation and consequently disrupted FAK-Src and PI3K interaction, providing a mechanism for the observed enhancement of invasion and spreading caused by merlin inactivation.

Accordingly, merlin was shown to reduce the levels of ErbB2 and ErbB3 receptor levels at the plasma membrane.

Accordingly, merlin was shown to reduce the levels of ErbB2 and ErbB3 receptor levels at the plasma membrane.

Accordingly, merlin was shown to reduce the levels of ErbB2 and ErbB3 receptor levels at the plasma membrane.

In sub-confluent primary Schwann cells, we found that merlin binds to paxillin and mediates merlin localization at the plasma membrane and association with beta1-integrin and ErbB2, modifying the organization of the actin cytoskeleton in a cell density dependent manner.

In sub-confluent primary Schwann cells, we found that merlin binds to paxillin and mediates merlin localization at the plasma membrane and association with β1-integrin and ErbB2, modifying the organization of the actin cytoskeleton in a cell density-dependent manner ( xref ).

Merlin-Amot interaction was required for merlin regulation of mitogenic MAPK signaling.

Moreover, in cultured Schwann cells, merlin interaction with Amot was demonstrated by co-immunoprecipitation of the endogenous proteins.

Moreover, in cultured Schwann cells, merlin interaction with Amot was demonstrated by co-immunoprecipitation of the endogenous proteins ( xref ).

Moreover, co-immunoprecipitation experiments revealed that merlin interacts with YAP1, although the interaction is not direct.

Moreover, co-immunoprecipitation experiments revealed that merlin interacts with YAP1, although the interaction is not direct ( xref ).

Studies in human meningioma tumors and in paired cell lines—KY21MG1 or MENII-1 meningioma cell lines and AC1 arachnoidal cells—demonstrated that merlin loss was associated with increased YAP expression and nuclear localization.

Amot-p130 isoform bound to the WW domains of YAP and blocked LATS1 access to YAP.

The activation of Rac1 through CD44 was identified via the interaction of CD44 with Tiam-1, a Rac1 guanine nucleotide exchange factor (GEF) that catalyzes the replacement of the tightly-bound GDP with GTP.

Merlin inactivation of Src signaling was also shown in CNS glial cells, where merlin competitively inhibits Src binding to ErbB2 thereby preventing ErbB2-mediated Src phosphorylation and downstream mitogenic signaling.

Merlin inactivation of Src signaling was also shown in CNS glial cells, where merlin competitively inhibits Src binding to ErbB2 thereby preventing ErbB2 mediated Src phosphorylation and downstream mitogenic signaling.

Merlin interacts with tubulin and acetylated-tubulin and stabilizes the microtubules by attenuating tubulin turnover -- lowering the rates of microtubule polymerization and depolymerization.

Merlin interacts with tubulin and acetylated-tubulin and stabilizes the microtubules by attenuating tubulin turnover—lowering the rates of microtubule polymerization and depolymerization.

Merlin inhibits PI3K activity by binding phosphatidylinositol 3-kinase enhancer-L (PIKE-L), the GTPase that binds and activates PI3K.

HDAC inhibitors disrupt the PP1-HDAC interaction facilitating Akt dephosphorylation and decrease human meningioma and schwannoma cell proliferation and schwannoma growth in an allograft model and meningioma growth in an intracranial xenograft model ( xref , xref , xref ).

In various cell types, the binding of hyaluronan to CD44 stimulates Tiam1 dependent Rac1 signaling and cytoskeleton mediated tumor cell migration.

Hyaluronan-CD44 interaction in astrocytes and an immortalized mouse mammary epithelial cell line, EpH4, leads to Rac1 signaling activation and actin cytoskeleton rearrangement ( xref , xref ).

In various cell types, the binding of hyaluronan to CD44 stimulates Tiam1 dependent Rac1 signaling and cytoskeleton mediated tumor cell migration.

Pharmacological or genetic inhibition of Rac1 in Nf2 -/- MEFs reduced the Wnt signaling activation to basal levels as assessed by reporter assay of transactivation of the nuclear beta-catenin-dependent T-cell factor 4 transcription factor.

In sub-confluent primary Schwann cells, we found that merlin binds to paxillin and mediates merlin localization at the plasma membrane and association with beta1-integrin and ErbB2, modifying the organization of the actin cytoskeleton in a cell density dependent manner.

In sub-confluent primary Schwann cells, we found that merlin binds to paxillin and mediates merlin localization at the plasma membrane and association with beta1-integrin and ErbB2, modifying the organization of the actin cytoskeleton in a cell density dependent manner.

FAK silencing decreased schwannoma cell proliferation and was associated with increased levels of total and nuclear p53.

In a similar fashion, NF2 mutations increased the resistance to dihydrofolate reductase inhibitors methotrexalate and pyremethamine as well as the JNK inhibitor JNK-9L.

Furthermore, it was shown that overactive PAK and LIMK pathway activity contributed to cell proliferation through cofilin phosphorylation and auroraA activation.

Interestingly, it was shown that schwannoma cells release insulin like growth factor binding protein 1 which in beta1-integrin dependent manner activates Src and FAK signaling.

Interestingly, it was shown that schwannoma cells release insulin like growth factor binding protein 1 which in beta1-integrin dependent manner activates Src and FAK signaling.

Moreover, neuregulin survival signaling through the ErbB2 and ErbB3 receptor activates PI3K in rat Schwann cells through the activation of Akt and inhibition of Bad, a pro apoptotic Blc-2 family protein.

ErbB2 activation in mouse Nf2 deficient spinal cord neural progenitor cells was shown to be caused by Rac mediated retention of the receptor at the plasma membrane.

Silencing DCAF1 in Meso-33, merlin deficient mesothelioma cells reduced their proliferation by arresting the cell cycle in G1 phase.

Significantly, silencing of DCAF1 in schwannoma cells isolated from NF2 patients also reduced their proliferation.

Silencing DCAF1 in Meso-33, merlin deficient mesothelioma cells reduced their proliferation by arresting the cell cycle in G1 phase.

Furthermore, Amot silencing attenuated Rac1 and Ras and MAPK signaling pathway.

Silencing of Amot in Nf2 -/- Schwann cells (SC4) selectively reduced cell proliferation because it did not change the proliferation rate of SC4 with merlin re-expression.

Furthermore, Amot silencing attenuated Rac1 and Ras and MAPK signaling pathway.

Furthermore, Amot silencing attenuated Rac1 and Ras and MAPK signaling pathway.

In various cell types, the binding of hyaluronan to CD44 stimulates Tiam1 dependent Rac1 signaling and cytoskeleton mediated tumor cell migration.

In various cell types, the binding of hyaluronan to CD44 stimulates Tiam1 dependent Rac1 signaling and cytoskeleton mediated tumor cell migration.

First, protein kinase C potentiated phosphatase inhibitor (CPI-17), which is frequently overexpressed in mesothelioma tumors, inhibits merlin phosphatase MYPT1-PP1delta, providing one potential pathway by which merlin 's tumor suppressor function might be inactivated through maintenance of phosphorylation at Ser518.

First, protein kinase C potentiated phosphatase inhibitor (CPI-17), which is frequently overexpressed in mesothelioma tumors, inhibits merlin phosphatase MYPT1-PP1delta, providing one potential pathway by which merlin 's tumor suppressor function might be inactivated through maintenance of phosphorylation at Ser518.

In various cell types, the binding of hyaluronan to CD44 stimulates Tiam1 dependent Rac1 signaling and cytoskeleton mediated tumor cell migration.

Finally, a recent meningioma study of 73 patients found a high incidence of TERT promoter activating mutations in meningiomas undergoing malignant transformation in both NF2-related and sporadic meningiomas, whereas no TERT mutations were found in benign tumors.

We recently showed that PI3K inhibition in merlin deficient mouse Schwann cells selectively decreased their proliferation.

In primary rat Schwann cells, CD44 was shown to constitutively associate with the heterodimer receptor tyrosine kinase ErbB2 and ErbB3 and CD44 enhanced neuregulin induced ErbB2 activating phosphorylation.

Moreover, neuregulin survival signaling through the ErbB2 and ErbB3 receptor activates PI3K in rat Schwann cells through the activation of Akt and inhibition of Bad, a pro apoptotic Blc-2 family protein.

In the canonical hippo pathway, mammalian Ste20 like kinases (Mst1/2; hippo homolog) phosphorylate large tumor suppressor kinases (LATS 1/2), which in turn phosphorylate and inactivate YAP and TAZ, blocking their role as TEAD and MEAD transcription factor co-activators.

SOS is a GEF that activates Ras by catalyzing the nucleotide exchange.

Further, NF-kB inhibition by overexpression of IkB also results in S15 phosphorylation of mutant p53 via GADD45α mediated JNK1 activation ( xref ).

Chronic S15 phosphorylation of mutant p53 has been found in tumors where DNA damage signaling is constitutively activated ( xref , xref ).

On the contrary , Nanog suppresses p53 activity while Gli activated by Nanog inhibits p53 by activating Mdm2 to promote pluripotency .

For example , p53 repress CD133 by directly binding to its promoter and recruiting HDAC1 ( Figure 2 ) .

p53 loss upregulates CD133 which subsequently promotes CSC marker expression and confers stemness .

With the advent of reprogramming era , it was further highlighted that p53 loss promote dedifferentiation and reprogramming under favorable conditions .

Furthermore, p53 loss was found to trigger dedifferentiation of mature hepatocytes to pluripotent cells by the activation of SC marker Nestin, which remains suppressed in wild-type p53 bearing cells (XREF_FIG).

With the advent of reprogramming era, it was further highlighted that p53 loss promote dedifferentiation and reprogramming under favorable conditions.

TP53 maintains homeostasis between self-renewal and differentiation depending on the cellular and developmental state and prevents the dedifferentiation and reprogramming of somatic cells to stem cells.

Loss or gain-of-function mutations in TP53 induce dedifferentiation and proliferation of SCs with damaged DNA leading to the generation of CSCs.

Also , upon DNA damage , p53 primarily promotes differentiation by suppression of Nanog .

Association of p53 inactivation and loss of differentiation characteristics has also been reported in AML and lung cancer (XREF_FIG).

Mutant p53 mediated repression of p63 function can also modulate the expression of certain miRNAs involved in invasion and metastasis such as let-7i, miR-155, miR-205, miR-130b, and miR-27a (XREF_FIG).

Mutant p53 can itself disrupt the balance between stem cell proliferation and differentiation as well as sequester p63 or p73 thereby hindering apoptosis, augmenting proliferation, and driving chemoresistance and metastasis typical of cancer stem cells.

Hence, loss of NUMB in breast cancer cells leads to decreased p53 levels and increased activity of NOTCH receptor which confers increased chemoresistance.

It may form a complex with mutant p53 and MDM2 to block their ubiquitination mediated degradation or may form a complex with mutant p53 to prevent aggregation of mutant p53 by inhibiting MDM2 and CHIP in multiple cancer cell lines ( xref , xref ).

A recent study by Capaci et al. showed that mutant p53 can interact with HIF1α to induce miR-30d expression which promotes tubulo-vesiculation of Golgi apparatus leading to enhanced vesicular trafficking and secretion ( xref ) ( xref ).

Binding of mutant p53 to ETS2 can promote expression of Pla2g16 or nucleotide synthesis genes required for invasion depending upon the cancer type ( xref ) ( xref , xref ).

Furthermore, the binding of mutant p53 to EGR1 promotes MYO10 expression which drives breast cancer cell invasion ( xref ) ( xref ).

Further, mutant p53 can interact with PELP1 to promote resistance to platinum-based drugs in triple negative breast cancer ( xref ).

A further study reported that mutant p53 enhance the association of mutant p53 and PARP on the replicating DNA ( xref ) ( xref ).

GOF mutant p53 can bind to TopBP1 and attenuate ATR checkpoint response during replication stress ( xref ) ( xref ).

The compound, RETRA disrupts mutant p53-p73 complex restoring p73-dependent transcription and apoptosis ( xref ) ( xref ).

Short Interfering Mutant p53 Peptides (SIMP) can interact with different mutant p53 proteins and release p73, while peptides aptamers (PA) can inhibit mutant p53 transcription ( xref ) ( xref ).

Mutant p53 and p63 complex can increase RAB coupling protein (RCP)-mediated recycling of cell surface growth promoting receptors.

Zhou et al. showed that mutant p53 binds to novel interacting partner AMPKα in glucose starvation conditions and inhibits its activation by other kinases leading to increased aerobic glycolysis, lipid production, and cell growth ( xref ) ( xref ).

This eliminates mitochondria-associated p53 which would otherwise be activated by PINK1 to mediate suppression of Nanog ( xref ) ( xref ).

This eliminates mitochondria associated p53 which would otherwise be activated by PINK1 to mediate suppression of Nanog (XREF_FIG).

Further, the human p53 isoform Delta133p53beta lacking the transactivation domain was observed to promote CSC features in breast cancer cell lines by expression of Sox2, Oct3/4, and Nanog in a Delta133p53beta dependent manner.

Acetylation of p53 at K373 by CBP and p300 leads to dissociation of HDM2 and TRIM24 and subsequent activation of p53 which in turn transcriptionally activates p21, miR-34a, and miR-145 (XREF_FIG).

Additionally , p53 upregulates miR-34a that represses Notch ( Figure 2 ) and anti-apoptotic Bcl2 thereby promoting differentiation and apoptosis ( 82 ) .

Further , induction of miR-34a by p53 functionally targets the CSC marker CD44 , thereby inhibiting prostate cancer regeneration and metastasis ( Figure 2 ) ( 74 ) .

Acetylation of p53 at K373 by CBP/p300 leads to dissociation of HDM2 and TRIM24 and subsequent activation of p53 which in turn transcriptionally activates p21, miR-34a, and miR-145 ( xref ).

Acetylation of p53 at K373 by CBP and p300 leads to dissociation of HDM2 and TRIM24 and subsequent activation of p53 which in turn transcriptionally activates p21, miR-34a, and miR-145 (XREF_FIG).

A recent study by Alam et al. reveals GOF mutant p53 upregulates EFNB2 and activates ephrin B2 reverse signaling to impart enhanced chemoresistance to colorectal cancer cells ( xref ) ( xref ).

Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming .

Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming .

Various transcription factors such as NF-Y, SREBPs, ETS, and EGFR1 play crucial role in mutant p53 driven invasion and metastasis.

Mutant p53 implicate various context and tissue dependent mechanisms to promote cancer cell invasion and metastasis.

Various transcription factors such as NF-Y, SREBPs, ETS, and EGFR1 play crucial role in mutant p53 driven invasion and metastasis.

Mutant p53 implicate various context and tissue dependent mechanisms to promote cancer cell invasion and metastasis.

This suggests that acetylation at K320 and K373 can alter the structure of mutant p53 and restore wild type p53 functions.

Mutant p53 can also induce YAP and TAZ nuclear localization by interacting with SREBP and activating the mevalonate pathway.

Mutant p53 can also promote proliferation by inducing the REG-gamma proteosome pathway in association with p300 (XREF_FIG).

GOF mutant p53 can modify the tumor microenvironment and has been found to support chronic inflammation.

While wild type p53 suppresses inflammatory response by inhibiting the production of cytokines and antagonizing NF-kB activity, mutant p53 on the other hand enhances NF-kB activity in response to TNF-alpha and promotes inflammation (XREF_FIG).

Several evidence demonstrate that mutant p53 promotes glycolysis and reprograms the cellular metabolism of cancer cells.

In absence of AMPK, mitochondrial stress augments aerobic glycolysis, also called " Warburg effect " in tumor cells, which is promoted by mutant p53.

Although these studies highlight that mutant p53 mediated EMT phenotype confer stemness in cancer cells, however, there is still a lot to explore in context of molecular mechanisms of mutant p53 driven stemness through activation of EMT genes.

Gain-of function mutant p53 further promotes EMT and stemness phenotypes by activating genes regulating them.

However, whether mutant p53 induced EMT trigger stemness properties in cancer cells, is still quite unexplored.

The sustained activation of NF-kB signaling by mutant p53 not only elevate inflammatory response but also protects the cancer cells from cytotoxic effects of tumor microenvironment by activating pro survival pathways.

While wild type p53 suppresses inflammatory response by inhibiting the production of cytokines and antagonizing NF-kB activity, mutant p53 on the other hand enhances NF-kB activity in response to TNF-alpha and promotes inflammation (XREF_FIG).

Interaction of mutant p53 to SREBPs activates mevalonate pathway that promotes invasion in breast cancer cells (XREF_FIG).

Mutant p53 can also induce YAP and TAZ nuclear localization by interacting with SREBP and activating the mevalonate pathway.

Similarly, p53 activation by nutlin leads to transcriptional activation of p21 that cause cell cycle arrest and induces differentiation in human ESCs.

Similarly , p53 activation by nutlin leads to transcriptional activation of p21 that cause cell cycle arrest and induces differentiation in human ESCs ( 35 ) .

Acetylation of p53 at K373 by CBP/p300 leads to dissociation of HDM2 and TRIM24 and subsequent activation of p53 which in turn transcriptionally activates p21, miR-34a, and miR-145 ( xref ).

Increased Expression of EZH2 Is Mediated by Higher Glycolysis and mTORC1 Activation in Lupus CD4 + T Cells.

Increased Expression of EZH2 Is Mediated by Higher Glycolysis and mTORC1 Activation in Lupus CD4

In summary, our findings suggest that EZH2 overexpression in SLE CD4 + T cells is induced by mTORC1 activation and increased glycolysis through effects on post-transcriptional regulation by miR-26a and miR-101 (XREF_FIG).

Increased Expression of EZH2 Is Mediated by Higher Glycolysis and mTORC1 Activation in Lupus CD4 + T Cells.

Indeed, inhibiting mTORC1 increased miR-26a and miR-101 and suppressed EZH2 expression in SLE CD4 + T cells.

Increased Expression of EZH2 Is Mediated by Higher Glycolysis and mTORC1 Activation in Lupus CD4

There are three potential mechanisms to explain these paradoxical findings : ( 1 ) Oxidative stress can induce EZH2 expression by additional mechanisms independent of our suggested mTORC1 / glycolysis / miRNA axis ; ( 2 ) A negative feedback homeostasis loop may exist to suppress EZH2 via miR-26a and miR-101 as EZH2 levels were significantly increased about 40 folds with oxidative stress ; and ( 3 ) miR-26a and miR-101 could be directly regulated by oxidative stress independent of mTORC1 / glycolysis .

These results suggest that oxidative stress upregulated EZH2 expression , via mechanisms that might be independent of post-transcriptional regulation by miR-26a and miR-101 .

EZH2 mediates abnormal CD4 + T cells adhesion in SLE by epigenetic dysregulation of the junctional adhesion molecule A (JAM-A) [XREF_BIBR].

The mechanisms underlying EZH2 upregulation in SLE CD4 + T cells remain unknown.

This is consistent with EZH2 mediated epigenetic changes in naive CD4 + T cells that were previously observed when SLE becomes more active [XREF_BIBR].

Increased disease activity in SLE patients is associated with a proinflammatory epigenetic shift in naive CD4 + T cells, likely mediated by EZH2.

EZH2 mediates abnormal CD4 + T cells adhesion in SLE by epigenetic dysregulation of the junctional adhesion molecule A (JAM-A) [XREF_BIBR].

In summary, our findings suggest that EZH2 overexpression in SLE CD4 + T cells is induced by mTORC1 activation and increased glycolysis through effects on post-transcriptional regulation by miR-26a and miR-101 (XREF_FIG).

Increased EZH2 is mediated by activation of mTORC1 and increased glycolysis in SLE CD4 + T cells.

Conclusion : Increased EZH2 is mediated by activation of mTORC1 and increased glycolysis in SLE CD4 + T cells .

Increased EZH2 is mediated by activation of mTORC1 and increased glycolysis in SLE CD4 + T cells .

Taken together, these data suggest that increased mTORC1 activity in SLE CD4 + T cells might mediate upregulation of EZH2 through increasing glycolysis and the resulting suppression of miR-26a and miR-101.

Because mTORC1 is activated in SLE CD4 + T cells in part due to increased oxidative stress , and mTORC1 activation increases glycolysis , we hypothesized that mTORC1 mediates increased EZH2 expression .

Because mTORC1 is activated in SLE CD4 + T cells in part due to increased oxidative stress , and mTORC1 activation increases glycolysis , we hypothesized that mTORC1 mediates increased EZH2 expression .

Increased EZH2 is mediated by activation of mTORC1 and increased glycolysis in SLE CD4 + T cells.

Mechanically, they elucidated that YC-1 facilitates E3-ligase c-Cbl phosphorylation at T731 and T774, leading to the activation of c-Cbl and complex formation with EZH2, and then EZH2 ubiquitination degradation.

A series of small molecules have been shown to facilitate EZH2-ubiquitination degradation.

As we discussed, the PTM of the EZH2-ubiquitination pathway is an important negative regulator of EZH2.

For instance, CDK1-mediated pT345-EZH2 and pT487-EZH2 facilitate EZH2 ubiquitination degradation in breast cancer cell, cervical cancer cell and lung cancer cell [ xref , xref , xref ]; JAK2 phosphorylates Y641-EZH2, leading to E3 ligase β-TrCP-mediated EZH2 degradation in lymphoma cell [ xref ]; and CDK5 phosphorylation of EZH2 at T261 residue results in the E3 ubiquitin ligase FBW7-mediated degradation of EZH2 in pancreatic cancer cell [ xref ].

Mechanistically, YC-1 treatment promotes c-Cbl phosphorylation at T731 and T774, which results in c-Cbl-induced Src and ERK activation, leading to the formation of the c-Cbl-ERK-EZH2 complex and the consequent accumulation of EZH2 ubiquitination and proteasomal degradation.

The first research of EZH2 ubiquitination was from the Aaron lab’s work in 2011 [ xref ].

Ubiquitination, sumoylation, and deubiquitination of EZH2 in tumorigenesis and cancer metastasis.

We showed that R342-EZH2 methylation inhibits TRAF6-mediated EZH2 ubiquitination [ xref ].

Another recent study has reported that CDK5-mediated T261-EZH2 phosphorylation facilitates FBW7-mediated EZH2 ubiquitination and proteasome degradation in pancreatic cancer cells [ xref ].

Moreover, researchers demonstrated that E3 ligase CHIP can mediate EZH2 ubiquitination degradation and subsequently derepress EZH2-silenced tumor suppressor genes by attenuating the H3K27me3 level in head and neck cancer cells [ xref ].

They found that pT345-EZH2 and pT487-EZH2 facilitate EZH2 ubiquitination and hence its degradation by the proteasome pathway in human cervical cancer cells [ xref ].

Our recent study has also confirmed that CDK1-mediated pT345-EZH2 and pT487-EZH2 facilitate EZH2 ubiquitination and subsequent degradation in breast cancer [ xref ].

Moreover, a recent report has revealed that SYDM2 catalyzes EZH2-K307 di-methylation attenuating EZH2-ubiquitination degradation in breast cancer [ xref ].

OGT-mediated O -GlcNAcylation of EZH2 attenuates EZH2 ubiquitination in breast cancer cell [ xref , xref ]; PCAF-mediated EZH2-K348 acetylation inhibits CDK1 catalyzing pT345-EZH2 and pT487-EZH2 and increases EZH2 stability in lung cancer [ xref ].

SETD2-mediated mono-methylation of EZH2-K735 promotes EZH2 ubiquitination in prostate cancer [ xref ].

They confirmed that circ-ADD3 binding with EZH2 facilitates CDK1-mediated EZH2 phosphorylation on T345 and T487, which results in EZH2 ubiquitination degradation in HCC cells.

Sun et al. found that circ-ADD3, as a circular RNA, inhibits hepatocellular carcinoma (HCC) metastasis through facilitating EZH2 degradation through CDK1-mediated EZH2 ubiquitination [ xref ].

Subsequently, the researchers designed a highly specific NEK2 inhibitor, CMP3a, which can promote EZH2 ubiquitination degradation and inhibit GBM tumor growth.

Ubiquitination, sumoylation, and deubiquitination of EZH2 in tumorigenesis and cancer metastasis.

A study showed that sumoylation of EZH2 is associated with EZH2 activity in U2OS cell (osteosarcoma cell line) [ xref ].

Moreover, another study demonstrated that JAK3-mediated EZH2 tyrosine (Y) Y244 phosphorylation, which suppresses PRC2 complex formation, resulting in EZH2 oncogenic function independent of its HMTase activity in natural killer/T-cell lymphoma (NKTL) [ xref ].

In addition, p38 catalyzing EZH2 phosphorylation at T367 residue elevates its localized to cytoplasm and promotes breast cancer cells distant metastasis [ xref ].

In addition, our recently studies discovered that PRMT1-mediated EZH2-R342 methylation attenuates CDK1-mediated EZH2-T345 and EZH2-T487 phosphorylation, which strengthens EZH2 stability [ xref , xref ].

They confirmed that circ-ADD3 binding with EZH2 facilitates CDK1-mediated EZH2 phosphorylation on T345 and T487, which results in EZH2 ubiquitination degradation in HCC cells.

Our recent research has illustrated that ANCR, a type of lncRNAs, promotes EZH2-T345 phosphorylation by associating with EZH2 [ xref ].

For instance, CDK1-mediated pT345-EZH2 and pT487-EZH2 facilitate EZH2 ubiquitination degradation in breast cancer cell, cervical cancer cell and lung cancer cell [ xref , xref , xref ]; JAK2 phosphorylates Y641-EZH2, leading to E3 ligase β-TrCP-mediated EZH2 degradation in lymphoma cell [ xref ]; and CDK5 phosphorylation of EZH2 at T261 residue results in the E3 ubiquitin ligase FBW7-mediated degradation of EZH2 in pancreatic cancer cell [ xref ].

For instance, CDK1 mediated pT345-EZH2 and pT487-EZH2 facilitate EZH2 ubiquitination degradation in breast cancer cell, cervical cancer cell and lung cancer cell [XREF_BIBR, XREF_BIBR, XREF_BIBR]; JAK2 phosphorylates Y641-EZH2, leading to E3 ligase beta-TrCP-mediated EZH2 degradation in lymphoma cell [XREF_BIBR]; and CDK5 phosphorylation of EZH2 at T261 residue results in the E3 ubiquitin ligase FBW7 mediated degradation of EZH2 in pancreatic cancer cell [XREF_BIBR].

Talha et al. [ xref ] revealed that p38 phosphorylated EZH2 at T367 site facilitating its cytoplasmic localization and interacting with vinculin and other cytoskeletal regulators of cell migration and invasion.

In 2018, Li et al. [ xref ] demonstrated that AMPK phosphorylates EZH2 at T311 residue to inhibit EZH2 binding with SUZ12, thereby attenuating the PRC2-dependent methylation of H3K27 and enhancing PRC2 target genes translation in ovarian and breast cancers.

In 2018, Li et al. [XREF_BIBR] demonstrated that AMPK phosphorylates EZH2 at T311 residue to inhibit EZH2 binding with SUZ12, thereby attenuating the PRC2 dependent methylation of H3K27 and enhancing PRC2 target genes translation in ovarian and breast cancers.

As early as 2005, Cha et al. [XREF_BIBR] showed phosphorylation of EZH2 at S21 (pS21-EZH2) by PI3K and AKT signaling in breast cancer cells.

SETD2-mediated mono-methylation of EZH2-K735 promotes EZH2 ubiquitination in prostate cancer [ xref ].

Furthermore, Kim et al. [ xref ] found that AKT-induced pS21-EZH2 elevates EZH2-mediated STAT3 methylation by increasing EZH2-STAT3 interaction in glioblastoma multiforme (GBM) stem-like cells.

In 2020, Yuan et al. [ xref ] reported that SETD2 methylates EZH2 at K735 promoting EZH2 degradation and impeding prostate cancer metastasis.

A study demonstrated that the phosphorylation of EZH2 at Y646 residue in human (Y641 in mouse) by JAK2 promotes the beta-TrCP-mediated EZH2 degradation and consequent regulation of H3K27me3 [XREF_BIBR].

In 2020, Yuan et al. [XREF_BIBR] reported that SETD2 methylates EZH2 at K735 promoting EZH2 degradation and impeding prostate cancer metastasis.

AKT-mediated pS21-EZH2 inhibits its methyltransferase activity by attenuating EZH2 associated with histone H3, which attenuates H3K27me3 level, increases EZH2 target genes expression, and facilitates breast cancer tumorigenesis.

Moreover , Jin et al. [ 50 ] revealed that FBW7 decreases EZH2 activity and attenuates the motility of pancreatic cancer cells by mediating the degradation of the EZH2 ubiquitin proteasome pathway .

Moreover, Jin et al. [XREF_BIBR] revealed that FBW7 decreases EZH2 activity and attenuates the motility of pancreatic cancer cells by mediating the degradation of the EZH2 ubiquitin proteasome pathway.

Recently , a report has confirmed that Praja1 degrades EZH2 during skeletal myogenesis [ 38 ] .

Aaron and his colleagues illustrated that Praja1 promotes EZH2 degradation through K48-linkage polyubiquitination and suppresses cells growth and migration in breast cancer [ 87 ] .

Silvia et al. [XREF_BIBR] revealed that p38alpha promotes E3 ligase Praja1 mediated EZH2 degradation through the phosphorylation of T372-EZH2 (T367-EZH2 in mouse).

This finding disclosed that Praja1 mediated EZH2 degradation is required for muscle satellite cells differentiation.

Recently, a report has confirmed that Praja1 degrades EZH2 during skeletal myogenesis [XREF_BIBR].

Aaron and his colleagues illustrated that Praja1 promotes EZH2 degradation through K48-linkage polyubiquitination and suppresses cells growth and migration in breast cancer [XREF_BIBR].

They found that Ub E3 ligase Praja1 mediates EZH2 protein degradation through the ubiquitination-proteasome pathway in MCF7 cells (breast cancer cell line).

A recent research has disclosed that sorafenib can prevent EZH2 expression by accelerating its ubiquitination-proteasome degradation in hepatoma cells [ 117 ] .

Moreover, NSC745885, as a small molecular, is derived from natural anthraquinone emodin, which can downregulate EZH2 via proteasome mediated degradation [XREF_BIBR].

Besides, Ma and his colleagues found that Ubiquitin specific protease 1 (USP1) directly interacts with and deubiquitinates EZH2.

For instance, EZH2 can promote the invasion and metastasis by suppressing E-cadherin transcriptional expression [XREF_BIBR, XREF_BIBR]; EZH2 can also increase tumorigenesis by silencing tumor suppressors [XREF_BIBR, XREF_BIBR, XREF_BIBR].

Reports on AKT-mediated pS21-EZH2 support the presumption that pS21-EZH2 mediated by AKT results in EZH2 promoting oncogenesis by several novel functions, which is independent on PRC2-mediated target gene transcriptional silencing.

Interestingly, arsenic-induced pS21-EZH2 is mainly cytoplasmic localization.

Instead of transcriptional repression EZH2 target gene expression, pS21-EZH2 serves as a transcriptional co-activator in castration-resistant prostate cancer through PI3K/AKT signaling [ xref ].

AKT-mediated pS21-EZH2 inhibits its methyltransferase activity by attenuating EZH2 associated with histone H3, which attenuates H3K27me3 level, increases EZH2 target genes expression, and facilitates breast cancer tumorigenesis.

As early as 2005, Cha et al. [ xref ] showed phosphorylation of EZH2 at S21 (pS21-EZH2) by PI3K/AKT signaling in breast cancer cells.

For instance, AKT-mediated pS21-EZH2 can promote breast cancer tumorigenesis [ xref , xref ].

They confirmed that the OGT-EZH2 axis inhibits tumor suppression by repressing the expression of several key tumor suppression genes in breast carcinoma.

They demonstrated that ZRANB1 can bind, deubiquitinate, and stabilize EZH2, which enhances breast cancer tumorigenesis and metastasis.

They demonstrated that ZRANB1 can bind, deubiquitinate, and stabilize EZH2, which enhances breast cancer tumorigenesis and metastasis.

We disclosed that ANCR-EZH2 interaction enhances CDK1 binding with EZH2 and increases the amount of pT345-EZH2, which results in EZH2 degradation and subsequently suppressing the oncogenesis and distant metastasis in breast cancer.

We disclosed that ANCR-EZH2 interaction enhances CDK1 binding with EZH2 and increases the amount of pT345-EZH2, which results in EZH2 degradation and subsequently suppressing the oncogenesis and distant metastasis in breast cancer.

Although AKT-mediated-EZH2-S21 phosphorylation reduces its affinity toward histone H3, it does not change its subcellular localization or its interaction with Polycomb group protein SUZ12 and EED subunits.

A study revealed that Smurf2 can interact with EZH2 and mediate EZH2 ubiquitination-proteasome degradation.

A study revealed that Smurf2 can interact with EZH2 and mediate EZH2 ubiquitination-proteasome degradation.

We speculate that ANCR-EZH2 association may change the conformation of EZH2, which probably facilitates the recognition and binding of CDK1 on EZH2 to phosphorylate its T345 residue.

We disclosed that ANCR-EZH2 interaction enhances CDK1 binding with EZH2 and increases the amount of pT345-EZH2, which results in EZH2 degradation and subsequently suppressing the oncogenesis and distant metastasis in breast cancer.

Furthermore, Kim et al. [ xref ] found that AKT-induced pS21-EZH2 elevates EZH2-mediated STAT3 methylation by increasing EZH2-STAT3 interaction in glioblastoma multiforme (GBM) stem-like cells.

It means that OGT mediated EZH2 GlcNAcylation have several different functions in breast cancer progression.Acetylation is a reversible and important PTM that regulates a series of cellular processes, including proliferation, apoptosis, migration, and metabolism, in cancer cells; it is achieved through the modulation of core histones or non histone proteins by histone acetyltransferases (HATs) or histone deacetylases (HDACs) [XREF_BIBR - XREF_BIBR].

This report also found that OGT mediated O GlcNAcylation at S75 stabilizes EZH2 and subsequently facilitates the formation of H3K27me3 on PRC2 target genes.

Professor Wong 's team first provided convincing evidence on OGT mediated EZH2 O GlcNAcylation at S75 in breast cancer [XREF_BIBR].