More relevantly, TLR4 is activated by viral PAMPs to initiate an innate immune and inflammatory response.

Inhibition of the NLRP3 inflammasome signalling pathway downstream of TLR4 attenuates LPS induced acute lung injury [XREF_BIBR, XREF_BIBR].

DAMP Mediated TLR4 Activation.

TLR4 activation by LPS on cardiomyocytes leads to subsequent reduction in myocardial contractility [XREF_BIBR, XREF_BIBR], and the predominant view in the literature is that TLR4 activation on cardiac structural fibroblasts and cardiac macrophages leads to a profibrotic and proinflammatory response, respectively [XREF_BIBR, XREF_BIBR].

Furthermore, while LPS increased TLR4 content in the lungs and heart by at least twofold, nifuroxazide was shown to significantly reduce TLR4 content by 45.7% in the lungs and 31.2% in the heart in the curative regimen and more so in the prophylactic regimen, compared to the LPS control [XREF_BIBR].

Additionally, it inhibited RSVF-, DENV-NS1-, and EBOV glycoprotein mediated TLR4 activation.

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

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).

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.

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).

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.

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).

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).

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.

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

This underscores the significance of PARP1 inhibitors (PARPi) to augment synthetic lethality in the context of mutant p53 mediated incapacitation of DNA repair (XREF_FIG).

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

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

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

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

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.

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).

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.

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

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

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

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).

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.

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

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).

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

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.

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

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.

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).

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

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

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

Growth Hormone Modulation of Hepatic Epidermal Growth Factor Receptor Signaling.

For instance, ubiquitination of NLRP3 by FBXL12, TRIM1, ARIH2 or the dopamine induced E3 ligase MARCH7 promotes the proteasomal degradation of NLRP3 in resting macrophages, whereas deubiquitylation of NLRP3 LRR domain on K63 by BRCC3 triggers ASC oligomerization and inflammasome activation (XREF_FIG).

Indeed, the LBD of VDR is able to physically interact with the NACHT-LRR domain of NLRP3 thus inhibiting the association of NLRP3 with BRCC3 and preventing NLRP3 deubiquitination (XREF_FIG).

For instance, ubiquitination of NLRP3 by FBXL12, TRIM1, ARIH2 or the dopamine induced E3 ligase MARCH7 promotes the proteasomal degradation of NLRP3 in resting macrophages, whereas deubiquitylation of NLRP3 LRR domain on K63 by BRCC3 triggers ASC oligomerization and inflammasome activation (XREF_FIG).

Together these data indicate that PPARgamma and Rev-erbalpha may inhibit NK-kappaB-dependent NLRP3 priming (XREF_FIG).

Indeed, while low extracellular Cl - enhances ATP induced IL-1beta secretion, high extracellular Cl - concentration or Cl - channel blockers inhibit NLRP3 activation.

For instance, ubiquitination of NLRP3 by FBXL12, TRIM1, ARIH2 or the dopamine induced E3 ligase MARCH7 promotes the proteasomal degradation of NLRP3 in resting macrophages, whereas deubiquitylation of NLRP3 LRR domain on K63 by BRCC3 triggers ASC oligomerization and inflammasome activation (XREF_FIG).

Interestingly, the bile acid receptor FXR is also able to physically interact with NLRP3 and Caspase1 thus inhibiting NLRP3 activity (XREF_FIG).

Furthermore, vitamin D enhances VDR mediated inhibition of NLRP3 activation.

Particularly, VDR has been shown to prevent NLRP3 modification on K63 and its subsequent activation.

Furthermore, vitamin D enhances VDR mediated inhibition of NLRP3 activation.

Since ROS scavengers attenuate NLRP3 activation, the generation of ROS was considered a common cellular response critical for NLRP3 activation.

In addition to caspase 1, cytosolic gram negative bacteria derived LPS may also be sensed independently of TLR4 signaling by human caspases 4 and 5, and mouse caspase 11, to induce the non canonical NLRP3 inflammasome.

In human hepatic hepG2 cell line, palmitic acid and LPS co-treatment induces the expression of NLRP3, NLRP6 and NLRP10 as well as Caspase 1 and IL-1beta.

In human hepatic hepG2 cell line, palmitic acid and LPS co-treatment induces the expression of NLRP3, NLRP6 and NLRP10 as well as Caspase 1 and IL-1beta.

For instance, ubiquitination of NLRP3 by FBXL12, TRIM1, ARIH2 or the dopamine induced E3 ligase MARCH7 promotes the proteasomal degradation of NLRP3 in resting macrophages, whereas deubiquitylation of NLRP3 LRR domain on K63 by BRCC3 triggers ASC oligomerization and inflammasome activation (XREF_FIG).

In addition, NLRP3 may also interact with mitochondrial antiviral signaling protein (MAVS), which is another mitochondrial outer MAM.

For instance, the NLRP3 and Caspase1 complex is able to cleave GR, thus impairing glucocorticoid activity in acute lymphoblastic leukemia (ALL) patients.

In addition, vitD3 dampens ASC speck formation by preventing the NLRP3 and NEK7 interaction.

Interestingly, in addition to LPS, the pro atherogenic apolipoprotein ApoC3 is able to trigger TLR2 and TLR4 heterodimerization and promotes the alternative activation of NLRP3, thus mirroring the effect of oxLDL in the canonical activation of NLRP3.

Then, the ASC adaptor accumulates at Mitochondria associated ER membranes (MAMs) where the NLRP3 and ACS complex is formed.

However, as HIF1alpha induces NLRP3 inflammasome activation, such regulatory mechanism may then account for LXR dependent activation of IL1-beta production in hypoxic atherosclerotic lesions.

Strikingly, ERbeta inhibits TNFalpha driven apoptosis and activates NLRP3 in endometriotic tissues.

Remarkably, inhibition of the NLRP3 inflammasome pathway reduces liver inflammation and fibrosis in an experimental mouse NASH model.

Intriguingly, Berberine inhibits NLRP3 activation in DSS induced colitis in a Rev-erbalpha-dependent manner.

Although the source of NLRP3 activating ROS was controversial, the inhibition of the lysosomal NADPH oxidase did not alter NLRP3 activation in mouse and human cells, thus suggesting an alternative source of NLRP3 activating ROS, likely the mitochondria.

Interestingly, human LPS primed macrophages treated with ATRA exhibit elevated NLRP3 RNA and protein levels associated with an increase in caspase 1 and pro-IL-1beta maturation.

This signaling pathway relies on a cascade involving TLR4, TIR domain containing adapter molecule 1 (TRIF), RIPK1, FADD and caspase 8 that finally promotes NLRP3 activation.

The priming step has two main purposes : the transcriptional induction of the inflammasome complex components NLRP3, Caspase 1, IL-1beta, and IL-18 and the induction of post-translational modifications of NLRP3 (XREF_FIG).

Two recent reports demonstrated that chloride intracellular channels (CLICs), especially CLIC1 and CLIC4 mediate NLRP3 activation by promoting Cl - efflux downstream nigericin induced K + efflux and mitochondrial ROS production, which promotes CLIC translocation to the plasma membrane (XREF_FIG).

Indeed, treatment of BMDM with bile acids suppresses LPS and Nigericin mediated NLRP3 activation in a TGR5-cAMP-PKA dependent by inducing NLRP3 ubiquitination and phosphorylation.

Accordingly, aldosterone induced renal tubular cell injury by activating NLRP3 in a mtROS dependent manner.

Epleronone abolishes aldosterone induced NLRP3, ASC, Casp1, and IL-18 maturation in mouse kidney, but the mechanism is still uncovered.

In this context, aldosterone promotes mtROS production and subsequent NLRP3 activation.

Altogether, VDR inhibits NLRP3 inflammasome by favoring NLRP3 ubiquitination, preventing NLRP3 assembly and reducing ROS mediated NLRP3 activation.

Nevertheless, RORgamma deletion in LPS primed BMDM inhibits NLRP3 and IL-1beta secretion, which is consistent with a RORgamma inhibiting effect of SR1555 and SR2211 on these processes.

Here, we demonstrate that epidermal growth factor receptor (EGFR) activation induces AKT dependent PCK1 pS90, PCK1 mediated INSIG1 pS207 and INSIG2 pS151, and nuclear SREBP1 accumulation in NSCLC cells.

Lapatinib, the small molecule tyrosine kinase inhibitor which targets HER2 and EGFR, has considerable anti-tumor activity against HER2+ BC cells, including trastuzumab resistant cells.

Given the fact that Lapatinib is a dual EGFR and HER2 inhibitor, we chose the HER2 overexpressing BC cell line, HCC-1954, and the EGFR overexpressing benign control cell line, MCF-10A, for further evaluation.

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.

In 2020, Yuan et al. [XREF_BIBR] 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].

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].

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].

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

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].

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

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

In vitro and in vivo studies confirmed that the abnormal increase of EZH2 can inhibit the expression level of E-cadherin, induce the epithelial stromal transformation of renal cancer cells, and promote the occurrence, development and recurrence of renal cancer.

EZH1 and EZH2 are the core components of PRC2, while EED can interact with EZH1 or EZH2 to maintain enzyme activity.

Studies have demonstrated that EZH2 can promote the development and metastasis of RCC.

Thus, inhibition of EZH2 can reduce the survival and invasion of clear cell renal cell carcinoma (ccRCC) cells and the growth of ccRCC in xenografted mice.

EZH2 also has growth promoting activity in RCC and can enhance the proliferation and invasion of renal tubular epithelial cells.

EZH2 inhibition elicits an anti-EMT effect related to preservation of E-cadherin expression, repression of transcription factors (i.e., Snail, twist), and deactivation of PTEN and Akt and beta-catenin signaling pathways.

EZH2 inhibition elicits an anti-EMT effect related to preservation of E-cadherin expression, repression of transcription factors (i.e., Snail, twist), and deactivation of PTEN and Akt and beta-catenin signaling pathways.

EZH2 also has growth promoting activity in RCC and can enhance the proliferation and invasion of renal tubular epithelial cells.

Moreover, EZH2 promotes cell proliferation, migration and angiogenesis by inhibiting expression of tumor suppressor genes such as p27Kip1 and enhancing expression of proto-oncogenes.

Blocking EZH2 by 3-DZNep and GSK126 can effectively inhibit the adhesion of lupus T cells to human microvascular endothelial cells.

In the same injury model, EZH2 inhibition also reduced renal dysfunction and tubular injury by regulating p38 signaling, apoptosis and inflammation.

In a murine model of cisplatin induced-AKI, inhibition of EZH2 expression by 3-DZNep could also reduce apoptosis of renal tubular cells and ameliorate acute renal injury by restoring expression of E-cadherin.

In the same injury model, EZH2 inhibition also reduced renal dysfunction and tubular injury by regulating p38 signaling, apoptosis and inflammation.

EZH2 inhibition elicits an anti-EMT effect related to preservation of E-cadherin expression, repression of transcription factors (i.e., Snail, twist), and deactivation of PTEN and Akt and beta-catenin signaling pathways.

Moreover, EZH2 promotes cell proliferation, migration and angiogenesis by inhibiting expression of tumor suppressor genes such as p27Kip1 and enhancing expression of proto-oncogenes.

In the same injury model, EZH2 inhibition also reduced renal dysfunction and tubular injury by regulating p38 signaling, apoptosis and inflammation.

EZH2 can also stimulate the expression of T cell multifunctional cytokines by activating the Notch pathway, and promoting T cell survival by Bcl-2 expression.

Emerging evidence has shown the role of EZH2 mediated histone modifications in AKI.

EZH2 inhibition elicits an anti-EMT effect related to preservation of E-cadherin expression, repression of transcription factors (i.e., Snail, twist), and deactivation of PTEN and Akt and beta-catenin signaling pathways.

For the degradation of EZH2, JAK2 phosphorylates EZH2 at tyrosine 641 [XREF_BIBR].

Based on these expression patterns and enhanced uterine epithelial proliferation in these mice, it was postulated that EZH2 suppresses differentiation of basal like cells and consequently restricts uncontrolled uterine epithelial proliferation.

Based on these expression patterns and enhanced uterine epithelial proliferation in these mice, it was postulated that EZH2 suppresses differentiation of basal like cells and consequently restricts uncontrolled uterine epithelial proliferation.

Whether EZH2 acts to repress or stimulate transcription largely relates to its association with other proteins.

In addition to determining that EZH2 promotes trophoblast invasion in JAR cells, the authors also found that EZH2 represses a tumor repressor gene that inhibits EMT, caudal type homeobox 1 (CDX1) [XREF_BIBR].

For example, EZH2 functions as a co-activator of estrogen receptor 1 (ESR1; also known as ERa) and promotes the transcription of its target genes.

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

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

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.

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.

The enhancer of zeste homolog 2 (EZH2) is a catalytic subunit of the polycomb repressive complex 2 (PRC2), acts as a histone methyltransferase and induces the trimethylation of histone H3 lysine 27 (H3K27me3) in the promoter of many key genes.

The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and induces the trimethylation of histone H3 lysine 27 (H3K27me3) in the promoter of many key genes; EZH2 acts as a transcriptional repressor and is an epigenetic regulator for several cancers.

The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and induces the trimethylation of histone H3 lysine 27 (H3K27me3) in the promoter of many key genes; EZH2 acts as a transcriptional repressor and is an epigenetic regulator for several cancers.

The enhancer of zeste homolog 2 (EZH2) is a catalytic subunit of the polycomb repressive complex 2 (PRC2), acts as a histone methyltransferase and induces the trimethylation of histone H3 lysine 27 (H3K27me3) in the promoter of many key genes.

The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and induces the trimethylation of histone H3 lysine 27 (H3K27me3) in the promoter of many key genes; EZH2 acts as a transcriptional repressor and is an epigenetic regulator for several cancers.

The inhibition of EZH2 aggravated cisplatin induced injury in renal tubular cells by inactivating mTOR complexes.

The present study showed that the inhibition of EZH2 induced apparent apoptosis in cultured NRK-52E cells, as demonstrated by flow cytometry and the concomitant increase of a pro apoptosis protein (cleaved-caspase 3) and decrease of anti-apoptosis proteins (Bcl-2 and HuR).

These data suggested that EZH2 inhibition induced notable apoptosis in NRK-52E cells.

Inhibition of EZH2 induced apoptosis in NRK-52E cells.

Thus, the regulation of Deptor expression by EZH2 may control cell growth and proliferation through mTOR complex pathways.

These data indicated that EZH2 inhibition decreased mTORC1 and mTORC2 activity by up-regulating Deptor expression.

In the present study, we identified that the inhibition of EZH2 with 3-deazaneplanocin A (DZNep) upregulated the transcription of Deptor by decreasing the H3K27me3 methylation level in its promoter region and reduced the activity of mTORC1 and mTORC2, resulting in apoptosis of NRK-52E cells.

These data suggested that EZH2 inhibition increased the transcription of Deptor by modifying H3K27me3 in its promoter region, subsequently inhibited mTORC1 and mTORC2 activities, downregulated the expression of apoptosis suppressor genes, and finally led to apoptosis in renal tubular cells.

In summary, our results showed that EZH2 inhibition increased the transcription level of Deptor by decreasing the level of trimethylation of H3K27 in the Deptor promoter region, subsequently inhibited the activities of mTORC1 and mTORC2, downregulated the expression of HuR and Bcl-2, and finally led to apoptosis in renal tubular cells.

EZH2 bound the Deptor promoter region and then regulated its transcriptional level.

A ChIP assay demonstrated that EZH2 bound the promoter region of Deptor, an endogenous inhibitor of mTORC1 and mTORC2, and regulated the transcription of Deptor by modulating H3K27me3 in its promoter region.

The binding of EZH2 to the Deptor promoter was determined by ChIPassay.

These data indicated that EZH2 inhibition decreased the activity of mTORC1 and mTORC2 activity.

Inhibition of EZH2 decreased the activity of mTORC1 and mTORC2.

These data indicated that HuR is situated between the mTOR complexes and Bcl-2 and that EZH2 inhibition might inactivate mTORC1 and mTORC2 in some manner, thus downregulating HuR and Bcl-2 expression and leading to cell apoptosis.

These data indicated that EZH2 inhibition decreased the activity of mTORC1 and mTORC2 activity.

Inhibition of EZH2 decreased the activity of mTORC1 and mTORC2.

These data indicated that HuR is situated between the mTOR complexes and Bcl-2 and that EZH2 inhibition might inactivate mTORC1 and mTORC2 in some manner, thus downregulating HuR and Bcl-2 expression and leading to cell apoptosis.