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.

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.

Translocation of merlin to the nucleus allows merlin to bind and inhibit the E3 ubiquitin ligase CRL4 DCAF1 (DDB1- and Cul4 Associated Factor 1).

Notably, NF2 transfection into these cells induced YAP1 phosphorylation at Ser127, YAP1 retention in the cytoplasm and consequent reduction of YAP1 nuclear localization.

Previously, we showed that activation of ErbB2 and ErbB3 receptors in primary rat Schwann cells by neuregulin-1 induced merlin phosphorylation at Ser518 via PKA.

Previously, we showed that activation of ErbB2 and ErbB3 receptors in primary rat Schwann cells by neuregulin-1 induced merlin phosphorylation at Ser518 via PKA.

Previously, we showed that activation of ErbB2 and ErbB3 receptors in primary rat Schwann cells by neuregulin-1 induced merlin phosphorylation at Ser518 via PKA.

We reported that merlin associates with beta 1 -integrin in primary Schwann cells and undifferentiated Schwann cell and neuron co-cultures, and in primary Schwann cell cultures, laminin-1 stimulated integrin signaled though PAK1 and caused merlin Ser518 phosphorylation and inactivation of its tumor suppressor function.

Merlin is phosphorylated at Ser10, Thr230 and Ser315 by Akt (also known as protein kinase B, PKB) and controls merlin 's proteasome mediated degradation by ubiquitination to prevent its interaction with binding partners.

Merlin is phosphorylated at Ser10, Thr230 and Ser315 by Akt (also known as protein kinase B, PKB) and controls merlin 's proteasome mediated degradation by ubiquitination to prevent its interaction with binding partners.

Merlin is phosphorylated at Ser10, Thr230 and Ser315 by Akt (also known as protein kinase B, PKB) and controls merlin 's proteasome mediated degradation by ubiquitination to prevent its interaction with binding partners.

Loss of merlin results in integrin mediated activation of mTORC1 through PAK1, which promotes cell cycle progression by inducing translation of cyclin-D1 mRNA and cyclin-D1 expression.

Adenoviral transduction of NF2 in Meso-17 and Meso-25 cell lines decreased invasion through Matrigel membranes compared to cells transduced with empty vector.

Loss of merlin in mesotheliomas has been linked not only to increased proliferation, but also increased invasiveness, spreading and migration.

Second, similar to NF2 schwannomas, mesothelioma cells with NF2 inactivation, exhibit activated PAK1 and AKT, and re-expression of merlin in merlin-null human mesothelioma cells (Meso-17) decreases PAK1 activity.

Soon after merlin was cloned, evidence that merlin inhibits another important member of the Rho GTPases family, Ras, was reported in v-Ha-Ras-transformed NIH3T3cells in which merlin overexpression counteracted the oncogenic role of Ras.

Merlin re-expression in Nf2 -/- Schwann cells similarly reduced the transport of growth factor receptors ErbB2 and ErbB3, insulin like growth factor 1 receptor (IGF1R) and platelet derived growth factor receptor (PDGFR).

Merlin re-expression in Nf2 -/- Schwann cells similarly reduced the transport of growth factor receptors ErbB2 and ErbB3, insulin like growth factor 1 receptor (IGF1R) and platelet derived growth factor receptor (PDGFR).

In sum, multiple lines of evidence have established a feedback regulation loop with merlin being phosphorylated at Ser518 (growth permissive form) via activated Rho small GTPases Rac1 and Cdc42 through PAK, and in turn, merlin associating with PAK to inhibit Rac1 and Cdc42 signaling (XREF_FIG).

Collectively, these results indicate that merlin inhibits cell growth by contact inhibition in part by binding CD44 and negatively regulating CD44 function (XREF_FIG).

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.

In the NF2 -/- breast cancer MDA-MB-231 cell line, merlin re-expression inhibited YAP and TEAD activity that was eliminated by LATS1/2 silencing.

Loss of merlin results in integrin mediated activation of mTORC1 through PAK1, which promotes cell cycle progression by inducing translation of cyclin-D1 mRNA and cyclin-D1 expression.

Loss of merlin activated mTORC1 signaling independently of Akt or ERK in these tumor cells; however, the molecular mechanism connecting merlin loss to mTORC1 activation remains to be elucidated.

Loss of merlin activated mTORC1 signaling independently of Akt or ERK in these tumor cells; however, the molecular mechanism connecting merlin loss to mTORC1 activation remains to be elucidated.

Furthermore, merlin overexpression in Tr6BC1 mouse schwannoma cells inhibited the binding of fluorescein labeled hyaluronan to CD44 and inhibited subcutaneous tumor growth in immunocompromised mice, and overexpression of a merlin mutant lacking the CD44 binding domain was unable to inhibit schwannoma growth.

Further studies showed that wild-type merlin is transported throughout the cell by microtubule motors and merlin mutants or depletion of the microtubule motor kinesin-1 suppressed merlin transport and was associated with accumulation of yorkie, a Drosophila homolog of the hippo pathway transcriptional co-activator Yes associated protein (YAP), in the nucleus.

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

The disrupted cell-contact inhibition signaling and merlin phosphorylation correlated with increased expression of NOTCH1 and its downstream target gene, HES1, which represses the transcription factor E2F in cell-contact growth arrest.

Binding of merlin unphosphorylated at Ser518 with the cytoplasmic tail of CD44 mediates contact inhibition at high cell density.

Loss of merlin activated mTORC1 signaling independently of Akt or ERK in these tumor cells; however, the molecular mechanism connecting merlin loss to mTORC1 activation remains to be elucidated.

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.

Loss of merlin results in integrin mediated activation of mTORC1 through PAK1, which promotes cell cycle progression by inducing translation of cyclin-D1 mRNA and cyclin-D1 expression.

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.

The mTORC1 inhibitor rapamycin selectively inhibited proliferation of seven merlin-null mesothelioma cell lines, but not merlin positive cell lines, suggesting a potential pharmacological target for merlin deficient mesotheliomas.

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.

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

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

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

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.

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.

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.

For instance, the interaction between HS and FGF2, a member of the fibroblast growth factor family, prefers the disaccharide unit of IdoA2S and GlcNS on heparin/HS.

, the authors claimed that the interaction between heparin and the S protein was independent of the anti-coagulant activity.

In support of the microarray data, SPR experiments showed that the SARS-CoV-2 S protein bound with higher affinity to heparin (K D = 55 nM) compared to the RBD (K D = 1 muM) alone.

The analysis revealed a conformational selection mechanism of GAGs binding and determined the structural specificity in the FGF1 and heparin complex.

During viral infection, a two-step sequential protease cleavage process triggers the activation of S proteins, which is modulated by host range and cell tropism.

Gao et al. reported that periodate oxidized, borohydride reduced heparin (RO-heparin) could inhibit thioglycollate induced peritoneal inflammation by preventing neutrophil recruitment dependent on the release of L- and P-selectin.

One person writing a tweet would still qualify for free-speech protections—but a million bot accounts pretending to be real people and distorting debate in the public square would not.

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.

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.

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

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).

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).

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.

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

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.

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.

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

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].

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.

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.

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.

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).

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].

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.

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

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].

This finding suggests that EZH2 can promote breast cancer metastasis through novel functions in cytoplasm.

EZH2 reportedly promotes cancer development and metastasis [XREF_BIBR, XREF_BIBR, XREF_BIBR].

A series of studies demonstrated that EZH2 can promote cancer tumorigenesis and metastasis independent on PRC2 mediated target gene silencing.

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

They also disclosed that pT350-EZH2 can elevate EZH2 mediated cell proliferation and migration.

A study reported that YC-1 decreases EZH2 expression and inhibits breast cancer cell proliferation via activation of its ubiquitination and proteasome degradation [XREF_BIBR].

Moreover, PCAF acetylates EZH2 at the K348 site promoting lung cancer tumorigenesis via stabilizing EZH2 [XREF_BIBR].

We further demonstrated that disruption of Trio or Myh9 inhibited Rac1 and Cdc42 activity, specifically affecting the nuclear export of beta-catenin and NCC polarization.

Because directional migration depends on the activation of small GTPases at the leading edge of cell protrusions and because Trio is a well-known GEF that likely acts upstream of the small GTPase family XREF_BIBR, XREF_BIBR, we evaluated whether Trio activated Rac1 and Cdc42 in NCC migration.

In this study, knockdown of EZH2 significantly inhibited TNBC cell proliferation and impaired cell migration and invasion, whereas overexpression of EZH2 produced an inverse phenotype.

Stable knockdown of EZH2 using lentiviral shRNA vector significantly reduced the proliferation, migration and invasion abilities of TNBC cell line MDA-MB-231 and MDA-MB-468, and downregulated NSD2 expression as well as the levels of H3K27me3 and H3K36me2, two histone methylation markers catalyzed by EZH2 and NSD2, respectively.

Based on the results of the present study, we speculated that EZH2 may enhance the transcription of NSD2 though interacting with some transcription factors or co-factors in TNBC.

A previous report suggested that the regulation of NSD2 expression by EZH2 may occur at the posttranscriptional level through microRNAs network.

EZH2 Mediated Oncogenic Effects Require NSD2 Expression.

By contrast, adenovirus mediated EZH2 overexpression significantly increased NSD2 expression as well as the methylation levels of H3K27 and H3K36 in MDA-MB-231 cells (XREF_FIG).

EZH2 Upregulates NSD2 Expression and Histone Methylation and Promotes the Proliferation, Migration, and Invasion of TNBC Cells.

Based on the PPI analysis (XREF_FIG), 45 genes interacted with EZH2 and seven genes interacted with NSD2.

The interaction of EZH2 and NSD2 was illustrated in vitro in the proliferation, migration, and invasion of TNBC cells.

EZH2 promotes the proliferation, migration and invasion abilities of TNBC cells via upregulating NSD2 expression.

In this study, knockdown of EZH2 significantly inhibited TNBC cell proliferation and impaired cell migration and invasion, whereas overexpression of EZH2 produced an inverse phenotype.

Ectopic overexpression of EZH2 induces malignant transformation of the mammary gland cells by promoting cell invasion and anchorage independent growth in vitro.

EZH2 promotes the proliferation, migration and invasion abilities of TNBC cells via upregulating NSD2 expression.

In this study, knockdown of EZH2 significantly inhibited TNBC cell proliferation and impaired cell migration and invasion, whereas overexpression of EZH2 produced an inverse phenotype.

EZH2 and NSD2 axis may contribute to the progression of TNBC by affecting the cell cycle pathway.

Furthermore, knockdown of NSD2 in EZH2 overexpressing cells could dramatically attenuate EZH2 mediated oncogenic effects.

This is the first report that knockdown of NSD2 abolishes EZH2 mediated TNBC cell proliferation, migration and invasion, indicating that the oncogenic function of EZH2 depends on NSD2 expression.

DDX11 expression was upregulated by the positive feedback loop of EZH2 and E2F1.

We thus speculated that EZH2 may cooperate with E2F1 to induce DDX11 transcription.

Our in vitro experiments showed that EZH2 could increase the mRNA expression of DDX11, which was significantly attenuated by the knockdown of E2F1.

As expected, DDX11 mRNA was upregulated by EZH2 overexpression, which was abolished by the knockdown of E2F1 (XREF_FIG).

In HCC cells, knockdown of E2F1 significantly decreased the mRNA expression of EZH2.

Several studies demonstrated that EZH2 could interacted with E2F1 to enhance its transcriptional activity.

In our study, DDX11 interacted with EZH2 to enhance its protein stability by avoiding the ubiquitination mediated protein degradation.

Further studies reveal that DDX11 interacts with EZH2 in HCC cells to protect it from ubiquitination mediated protein degradation, consequently resulting in the downregulation of p21.

This manifests DDX11 was not required for the E2F1 mediated EZH2 regulation.

However, the expression of p53 and MDM2 remained unchanged (XREF_FIG), which may suggest a p53 independent manner of DDX11 mediated p21 alteration.

Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).