For instance , EZH2 can promote the invasion and metastasis by suppressing E-cadherin transcriptional expression [ 28 , 29 ] ; EZH2 can also increase tumorigenesis by silencing tumor suppressors [ 9 , 20 , 25 ] .

It means that EZH2 can activate gene expression and oncogenesis without being dependent on its methyltransferase activity .

For instance , EZH2 can promote the invasion and metastasis by suppressing E-cadherin transcriptional expression [ 28 , 29 ] ; EZH2 can also increase tumorigenesis by silencing tumor suppressors [ 9 , 20 , 25 ] .

EZH2 reportedly promotes cancer development and metastasis [ 9 , 17 , 18 ] .

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

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].

For instance , EZH2 can promote the invasion and metastasis by suppressing E-cadherin transcriptional expression [ 28 , 29 ] ; EZH2 can also increase tumorigenesis by silencing tumor suppressors [ 9 , 20 , 25 ] .

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].

Recently, Wan et al. [ xref ] have elucidated that EZH2-K348 residue is acetylated by acetyltransferase P300/CBP-associated factor (PCAF) and is deacetylated by deacetylase SIRT1 in lung cancer cells.

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.

Dissecting the functional roles of Trio and Myh9 in NCCs 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 31 , 32 , we evaluated whether Trio activated Rac1 and Cdc42 in NCC migration .

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.

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 , xref , we evaluated whether Trio activated Rac1 and Cdc42 in NCC migration.

Desmoplastic small round cell tumor (DSRCT) is characterized by the EWSR1-WT1 t(11;22) (p13:q12) translocation.

EWSR1-WT1 fusions were noted to be simple, balanced events.

PDX models harbored the pathognomic EWSR1-WT1 fusion and were highly representative of corresponding tumors.

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.

Six genes interacting with both EZH2 and NSD2 were further identified, that were cyclin A2 (CCNA2), cyclin dependent kinase 2 (CDK2), lysine demethylase 2B (KDM2B), kinesin family member 11 (KIF11), kinesin family member 23 (KIF23), and proliferating cell nuclear antigen (PCNA) ( xref ).

The interaction of EZH2 and NSD2 was illustrated in vitro in 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.

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 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.

Thus, we next checked whether the binding of DDX11 and EZH2 may affect the ubiquitination of EZH2 in HCC cells.

Results demonstrated that the ubiquitination of EZH2 protein was obviously enhanced by the depletion of DDX11 ( xref ).

Functionally , DDX11 promoted cell proliferation by inducing the expression of EZH2 , a famous oncogene ( 20 , 25 ) , to subsequently inhibit the expression of p21 , a well-known tumor suppressor .

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.

Thus, E2F1 and EZH2 formed a positive feedback loop to upregulate the expression of DDX11 in HCC cells.

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.

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

We next examined whether DDX11 bound to EZH2 in HCC cells.

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.

Thus, we next checked whether the binding of DDX11 and EZH2 may affect the ubiquitination of EZH2 in HCC cells.

Functionally , DDX11 promoted cell proliferation by inducing the expression of EZH2 , a famous oncogene ( 20 , 25 ) , to subsequently inhibit the expression of p21 , a well-known tumor suppressor .

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.

Fifty-eight B-other ALL patients (not BCR-ABL1 , KMT2A -rearranged, ETV6-RUNX1 , TCF3-PBX1 , or iAMP21) were included in the study.

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).

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).

CD103 binds E-cadherin, which is highly expressed on epithelia, whereas CD69 antagonizes sphingosine 1-phosphate receptor 1 (S1PR1)-mediated egress from tissues.

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).

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).

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).

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).

Further validating transcriptional data, CXCR3 expression was higher on CD8 + CD103 + CD49a + Trm cells, whereas IL-23R and CCR6 were preferentially expressed by CD8 + CD103 + CD49a - Trm cells (XREF_FIG G).

Further validating transcriptional data, CXCR3 expression was higher on CD8 + CD103 + CD49a + Trm cells, whereas IL-23R and CCR6 were preferentially expressed by CD8 + CD103 + CD49a - Trm cells (XREF_FIG G).

In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

Accordingly, IL-15-dependent expression of perforin and granzyme B was augmented by IL-6, but not other cytokine combinations tested (XREF_SUPPLEMENTARY C-S2E).

Rather, their cytotoxic capacity was primed through IL-2 and IL-15-mediated induction of perforin and granzyme B expression.

Rather, their cytotoxic capacity was primed through IL-2 and IL-15-mediated induction of perforin and granzyme B expression.

In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

Moreover, IL-15 stimulation potentiated TCR dependent expression of IL-17 and IFN-gamma by epidermal CD8 + CD103 + CD49a - and IFN-gamma by CD8 + CD103 + CD49a + Trm cells, respectively (XREF_FIG D), substantiating effectual gamma chain receptor signaling in both subsets.

In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

Further validating transcriptional data, CXCR3 expression was higher on CD8 + CD103 + CD49a + Trm cells, whereas IL-23R and CCR6 were preferentially expressed by CD8 + CD103 + CD49a - Trm cells (XREF_FIG G).

Further validating transcriptional data, CXCR3 expression was higher on CD8 + CD103 + CD49a + Trm cells, whereas IL-23R and CCR6 were preferentially expressed by CD8 + CD103 + CD49a - Trm cells (XREF_FIG G).

Moreover, IL-15 stimulation potentiated TCR dependent expression of IL-17 and IFN-gamma by epidermal CD8 + CD103 + CD49a - and IFN-gamma by CD8 + CD103 + CD49a + Trm cells, respectively (XREF_FIG D), substantiating effectual gamma chain receptor signaling in both subsets.

In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

CD103 binds E-cadherin, which is highly expressed on epithelia, whereas CD69 antagonizes sphingosine 1-phosphate receptor 1 (S1PR1)-mediated egress from tissues.

Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

Relative to the epidermal CD8 + CD103 + CD49a - Trm cells, dermal counterparts produced 3.5-fold less IL-17.

Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

Relative to the epidermal CD8 + CD103 + CD49a - Trm cells, dermal counterparts produced 3.5-fold less IL-17.

Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

In human skin epithelia, CD8 + CD49a + Trm cells produced interferon-gamma, whereas CD8 + CD49a - Trm cells produced interleukin-17 (IL-17).

Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

IL-2 and IL-15 Induce Cytotoxic Effector Protein Expression in Epidermal CD8 + CD103 + CD49a + Trm Cells.

Conversely, CD8 + CD49a - Trm cells from psoriasis lesions predominantly generated IL-17 responses that promote local inflammation in this skin disease.

This functional dichotomy was evident in the comparison of distinct immune mediated skin diseases, with skin biopsies from vitiligo patients showing a predominance of cytotoxic CD8 + CD103 + CD49a + Trm cells while skin biopsies from psoriasis patients featured the accumulation of the IL-17 producing CD8 + CD103 + CD49a - counterparts.

Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

Generally, IFN-gamma contributes to immunity toward intracellular infections while IL-17 provides anti-fungal defense and both of these cytokines initiate inflammatory keratinocyte responses.

In line withincreased CD49a frequencies, IFN-gamma producing Trm cells were enriched in vitiligo lesions (XREF_FIG G).

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).

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).

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).

TCR engagement using anti-CD3 antibodies also preferentially induced IFN-gamma by epidermal CD8 + CD103 + CD49a + Trm cells (XREF_FIG D).

Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

TNF and IL-2 were abundantly produced by dermal and epidermal Trm cell subsets (XREF_FIG B and 6C).

TNF and IL-2 were abundantly produced by dermal and epidermal Trm cell subsets (XREF_FIG B and 6C).

TNF and IL-2 were abundantly produced by dermal and epidermal Trm cell subsets (XREF_FIG B and 6C).

Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

In human skin epithelia, CD8 + CD49a + Trm cells produced interferon-gamma, whereas CD8 + CD49a - Trm cells produced interleukin-17 (IL-17).

Revealing functional specialization among epidermal Trm cells with respect to CD49a expression, CD8 + CD103 + CD49a - Trm cells preferentially produced IL-17, a cytokine required for control of bacterial and fungal infections.

Moreover, IL-17 or IFN-gamma production by distinct Trm cells subsets was generally maintained even in the context of the vigorous tissue inflammation.

Corroborating transcriptional profiles, CD8 + CD103 + CD49a - Trm cells produced IL-17 while CD8 + CD103 + CD49a + Trm cells excelled in IFN-gamma production upon stimulation with phorbol 12-myristate 13-acetate and ionomycin (XREF_FIG A-6C).

Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

In human skin epithelia, CD8 + CD49a + Trm cells produced interferon-gamma, whereas CD8 + CD49a - Trm cells produced interleukin-17 (IL-17).

Here, we identify CD49a expression as a marker delineating a subpopulation ofCD8 + Trm cells in human skin that specifically localize to thebasal layer of epidermis, preferentially produce IFN-gamma, and display high cytotoxic capacity upon stimulation.

Moreover, IL-17 or IFN-gamma production by distinct Trm cells subsets was generally maintained even in the context of the vigorous tissue inflammation.

TNF and IL-2 were abundantly produced by dermal and epidermal Trm cell subsets (XREF_FIG B and 6C).

The pre-metastatic niche also secretes factors that push cells towards dormancy, such as thrombospondin 1 (TSP1) deposited around microvasculature, which blocks tumour angiogenesis, and TGFbeta secreted by stromal cells that regulate cancer cell quiescence [XREF_BIBR].

Small molecule inhibitors such as MRTX849 have been identified as potent, selective KRAS G12C inhibitors to selectively modify mutant cysteine 12 in the GDP bound KRAS G12C mutant protein to inhibit signalling [XREF_BIBR].

Elevated levels of CXCL1 recruit CXCR2 positive MDSCs to the pre-metastatic liver tissue and promote tumour cell survival and metastasis while evading host immune responses [XREF_BIBR].

Elevated levels of CXCL1 recruit CXCR2 positive MDSCs to the pre-metastatic liver tissue and promote tumour cell survival and metastasis while evading host immune responses [XREF_BIBR].

LSECs secrete fibronectin that can induce EMT in colon cancer cells by enhancing ERK signalling, and human LSECs were shown to induce cell migration and EMT via MIF, thereby increasing the metastatic potential of colon cancer cells [XREF_BIBR, XREF_BIBR, XREF_BIBR].

They also secrete endothelin-1, which is a vasoconstrictor that promotes cell proliferation, fibrogenesis, and contraction linked to cirrhosis [XREF_BIBR].

Moreover, CXCR4 and TGFbeta blockade by AMD3100 inhibited the differentiation of HSCs to CAFs and significantly reduced metastatic burden in vivo [XREF_BIBR].

Accordingly, the co-treatment of galunisertib with anti-PD-L1 treatment induced an immune response characterised with elevated T-bet and IFNgamma levels in CD4 + T cells, increased GZMB production, along with increased infiltration into the tumours.

The prominence of IL-6 signalling in the liver as well as TGFbeta driven IL-11 signalling in supporting primary tumour growth and metastasis in preclinical models suggest that these cytokines play important roles in the outgrowth of hepatic metastases [XREF_BIBR, XREF_BIBR].