4,197 Matching Annotations
  1. Mar 2021
    1. 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 ].

      EZH2 is ubiquitinated.

    2. 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 ].

      EZH2 is ubiquitinated.

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

      EZH2 is ubiquitinated.

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

      EZH2 is ubiquitinated.

    5. 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 ].

      EZH2 is ubiquitinated.

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

      EZH2 is ubiquitinated.

    7. 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.

      EZH2 is ubiquitinated.

    8. 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 ].

      EZH2 is ubiquitinated.

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

      EZH2 is ubiquitinated.

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

      EZH2 is sumoylated.

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

      EZH2 is sumoylated.

    12. 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 ].

      EZH2 is phosphorylated on Y244.

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

      EZH2 is phosphorylated on T367.

    14. 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 ].

      EZH2 is phosphorylated on T345.

    15. 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.

      EZH2 is phosphorylated on T345.

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

      EZH2 is phosphorylated on T345.

    17. 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 ].

      CDK5 phosphorylates EZH2 on T261.

    18. 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].

      CDK5 phosphorylates EZH2 on T261.

    19. 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.

      p38 phosphorylates EZH2.

    20. 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.

      AMPK phosphorylates EZH2 on T311.

    21. 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.

      AMPK phosphorylates EZH2 on T311.

    22. 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.

      AKT leads to the phosphorylation of EZH2 on S21.

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

      EZH2 is methylated on K735.

    24. 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.

      EZH2 methylates STAT3.

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

      SETD2 methylates EZH2.

    26. 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].

      EZH2 inhibits EZH2.

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

      EZH2 inhibits EZH2.

    28. 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.
    29. 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 .

      FBXW7 inhibits EZH2.

    30. 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.

      FBXW7 inhibits EZH2.

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

      PJA1 inhibits EZH2.

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

      PJA1 inhibits EZH2.

    33. 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).

      PJA1 inhibits EZH2.

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

      PJA1 inhibits EZH2.

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

      PJA1 inhibits EZH2.

    36. 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].

      PJA1 inhibits EZH2.

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

      PJA1 inhibits EZH2.

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

      sorafenib inhibits EZH2.

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

      emodin inhibits EZH2.

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

      Protease deubiquitinates EZH2.

    41. 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].

      EZH2 decreases the amount of CDH1.

    42. 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.

      EZH2 binds PROS1.

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

      EZH2 binds PROS1.

    44. 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 ].

      EZH2 binds PROS1.

    45. 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.

      EZH2 binds PROS1.

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

      EZH2 binds PROS1.

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

      EZH2 binds PROS1.

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

      EZH2 binds OGT.

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

      ZRANB1 binds EZH2.

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

      ZRANB1 binds EZH2.

    51. 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.

      CDK1 binds EZH2.

    52. 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.

      CDK1 binds EZH2.

    53. 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.

      SUZ12 binds EED and EED.

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

      SMURF2 binds EZH2.

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

      SMURF2 binds EZH2.

    56. 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.

      UBE3A binds EZH2.

    57. 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.

      UBE3A binds EZH2.

    58. 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.

      STAT3 binds EZH2.

    59. 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].

      OGT activates EZH2.

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

      OGT activates EZH2.

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

      OGT activates EZH2.

    62. 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 activates Carcinogenesis.

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

      EZH2 activates Carcinogenesis.

    64. 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 ] .
    65. EZH2 reportedly promotes cancer development and metastasis [ 9 , 17 , 18 ] .
    66. They demonstrated that ZRANB1 can bind , deubiquitinate , and stabilize EZH2 , which enhances breast cancer tumorigenesis and metastasis .
    67. This finding suggests that EZH2 can promote breast cancer metastasis through novel functions in cytoplasm.
    68. EZH2 reportedly promotes cancer development and metastasis [XREF_BIBR, XREF_BIBR, XREF_BIBR].
    69. A series of studies demonstrated that EZH2 can promote cancer tumorigenesis and metastasis independent on PRC2 mediated target gene silencing.
    70. In addition, p38 catalyzing EZH2 phosphorylation at T367 residue elevates its localized to cytoplasm and promotes breast cancer cells distant metastasis [XREF_BIBR].
    71. 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 ] .
    72. They also disclosed that pT350-EZH2 can elevate EZH2 mediated cell proliferation and migration.
    73. 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].
    74. 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.

      KAT2B acetylates EZH2 on K348.

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

      KAT2B acetylates EZH2 on K348.

    1. 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.

      TRIO activates CDC42.

    2. 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 .

      TRIO activates CDC42.

    3. 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.

      TRIO activates CDC42.

    4. 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.

      TRIO activates CDC42.

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

      WT1 binds EWSR1.

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

      WT1 binds EWSR1.

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

      WT1 binds EWSR1.

    1. 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 inhibits cell migration.

    2. 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.

      EZH2 increases the amount of NSD2.

    3. 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.

      EZH2 increases the amount of NSD2.

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

      EZH2 increases the amount of NSD2.

    5. EZH2 Mediated Oncogenic Effects Require NSD2 Expression.

      EZH2 increases the amount of NSD2.

    6. 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 increases the amount of NSD2.

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

      EZH2 increases the amount of NSD2.

    8. 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 ).

      NSD2 binds EZH2.

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

      NSD2 binds EZH2.

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

      NSD2 binds EZH2.

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

      NSD2 binds EZH2.

    12. EZH2 promotes the proliferation, migration and invasion abilities of TNBC cells via upregulating NSD2 expression.
    13. 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.
    14. Ectopic overexpression of EZH2 induces malignant transformation of the mammary gland cells by promoting cell invasion and anchorage independent growth in vitro.
    15. 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 activates cell migration.

    16. EZH2 promotes the proliferation, migration and invasion abilities of TNBC cells via upregulating NSD2 expression.
    17. 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.
    18. EZH2 and NSD2 axis may contribute to the progression of TNBC by affecting the cell cycle pathway.

      EZH2 activates cell cycle.

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

      NSD2 activates EZH2.

    20. 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.

      NSD2 activates EZH2.

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

      EZH2 is ubiquitinated.

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

      EZH2 is ubiquitinated.

    3. 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 .

      EZH2 inhibits CDKN1A.

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

      EZH2 increases the amount of DDX11.

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

      EZH2 increases the amount of DDX11.

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

      EZH2 increases the amount of DDX11.

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

      E2F1 increases the amount of EZH2.

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

      E2F1 increases the amount of EZH2.

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

      E2F1 binds EZH2.

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

      E2F1 binds EZH2.

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

      E2F1 binds EZH2.

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

      DDX11 binds EZH2.

    13. 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.

      DDX11 binds EZH2.

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

      DDX11 binds EZH2.

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

      DDX11 binds EZH2.

    16. 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.

      DDX11 binds EZH2.

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

      DDX11 binds EZH2.

    18. 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 .
    19. This manifests DDX11 was not required for the E2F1 mediated EZH2 regulation.

      E2F1 activates EZH2.

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

      TP53 activates CDKN1A.

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

      RUNX1 binds ETV6.

    1. 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).

      IL23R inhibits ITGAE.

    2. 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).

      IL23R inhibits ITGA1.

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

      CD69 inhibits S1PR1.

    4. 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).

      IL17F inhibits ITGAE.

    5. 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).

      IL17F inhibits ITGA1.

    6. 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).

      CCRL2 inhibits ITGAE.

    7. 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).

      CCRL2 inhibits ITGA1.

    8. 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).

      ITGAE increases the amount of IL23R.

    9. 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).

      ITGAE increases the amount of CCRL2.

    10. 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.

      ITGA1 increases the amount of PRF1.

    11. 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.

      ITGA1 increases the amount of PRF1.

    12. 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.

      ITGA1 increases the amount of GZMB.

    13. 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).

      IL6 increases the amount of GZMB.

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

      IL2 increases the amount of PRF1.

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

      IL2 increases the amount of GZMB.

    16. 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.

      CD8 increases the amount of PRF1.

    17. 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.

      CD8 increases the amount of PRF1.

    18. 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.

      CD8 increases the amount of IL17A.

    19. 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.

      CD8 increases the amount of GZMB.

    20. 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).

      CD8 increases the amount of IL23R.

    21. 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).

      CD8 increases the amount of CCRL2.

    22. 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.

      CD8 increases the amount of TCR.

    23. 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.

      Trm increases the amount of PRF1.

    24. 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.

      Trm increases the amount of PRF1.

    25. 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.

      Trm increases the amount of GZMB.

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

      CDH1 binds ITGAE.

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

      IV activates ITGAE.

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

      IV activates IFNG.

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

      ITGAE activates IL17A.

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

      ITGA1 activates ITGAE.

    31. 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.

      ITGA1 activates IL17A.

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

      ITGA1 activates IL17A.

    33. 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.

      ITGA1 activates IFNG.

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

      ITGA1 activates IFNG.

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

      ITGA1 activates IFNG.

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

      ITGA1 activates Trm.

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

      IL2 activates Trm.

    38. Conversely, CD8 + CD49a - Trm cells from psoriasis lesions predominantly generated IL-17 responses that promote local inflammation in this skin disease.
    39. 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.

      IL17A activates CD8.

    40. 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.

      IL15 activates ITGAE.

    41. 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.

      IL15 activates ITGA1.

    42. 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.

      IFNG activates immune response.

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

      IFNG activates Trm.

    44. 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).

      IL23R activates IL17A.

    45. 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).

      IL17F activates IL17A.

    46. 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).

      CCRL2 activates IL17A.

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

      TCR activates Trm.

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

      CD8 activates ITGAE.

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

      CD8 activates ITGA1.

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

      CD8 activates Trm.

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

      Collagen activates ITGAE.

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

      Collagen activates IFNG.

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

      carbon atom activates IL2.

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

      carbon atom activates TNF.

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

      Trm activates IL2.

    56. 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.

      Trm activates IL17A.

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

      Trm activates IL17A.

    58. 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.

      Trm activates IL17A.

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

      Trm activates IL17A.

    60. 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).

      Trm activates IL17A.

    61. 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.

      Trm activates IFNG.

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

      Trm activates IFNG.

    63. 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.

      Trm activates IFNG.

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

      Trm activates IFNG.

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

      Trm activates TNF.

    1. 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].

      TGFB inhibits angiogenesis.

    2. 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].

      GDP binds KRAS-G12C.

    3. 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].
    4. 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].

      CXCL1 activates Cell Survival.

    5. 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].
    6. They also secrete endothelin-1, which is a vasoconstrictor that promotes cell proliferation, fibrogenesis, and contraction linked to cirrhosis [XREF_BIBR].
    7. Moreover, CXCR4 and TGFbeta blockade by AMD3100 inhibited the differentiation of HSCs to CAFs and significantly reduced metastatic burden in vivo [XREF_BIBR].
    8. 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.

      CD4 activates GZMB.

    9. 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].

      TGFB activates IL11.