EZH2 Regulates Protein Stability via Recruiting USP7 to Mediate Neuronal Gene Expression in Cancer Cells

Lei, Anhua; Chen, Lu; Zhang, Min; Yang, Xiaoli; Xu, Liyang; Cao, Ning; Zhang, Zan; Cao, Ying

doi:10.3389/fgene.2019.00422

Cited by 34 publications

(56 citation statements)

References 58 publications

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“…IF detection of marker proteins in cells, myotubes, neurospheres or neurosphere-like structures derived from cancer cells was performed exactly as described [11]. Primary antibodies were Myc (Cell Signaling, Flour 594 (ThermoFisher Scienti c, #A21207, #A21203.…”

Section: Immuno Uorescence (If)mentioning

confidence: 99%

“…gRNA target oligos were cloned to the BsmBI site of lentiCRISPRv2 vector. Lentivirus packaging was performed as described [11]. C2C12 cells were infected with lentiviral particles containing the gRNA target and selected with puromycin (1 mg/ml) for three days.…”

Section: Immuno Uorescence (If)mentioning

confidence: 99%

“…We showed previously that cells of different cancer types were characteristic of neural stem/progenitor cells (NSCs/NPCs) because 1) cancer cells exhibit neuronal differentiation potential when endogenous cancer-promoting factors are inhibited, and 2) expression of most (if not all) cancer promoting genes or genes being upregulated/activated in cancer cells is neural speci c or at least enriched in embryonic neural cells [10,11]. In contrast, a substantial part of cancer repressor genes or the genes downregulated/silenced in cancer cells is expressed in non-neural cells or is not expressed in embryos [10].…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, a substantial part of cancer repressor genes or the genes downregulated/silenced in cancer cells is expressed in non-neural cells or is not expressed in embryos [10]. Major genes/factors that regulate cancer cell malignant features are also expressed speci cally in embryonic neural cells and/or play critical roles in neural development [10][11][12]. The similarity in regulatory network is not found between cancer cells and other types of cells, e.g., the mesenchymal cells.…”

Section: Introductionmentioning

confidence: 99%

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Neural stemness contributes to cell tumorigenicity

Zhang

Shi

et al. 2020

Preprint

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Background Previous studies demonstrated the dependence of cancer on nerve. Recently, a growing number of studies reveal that cancer cells share the property and regulatory network with neural stem/progenitor cells. However, relationship between the property of neural stemness and cell tumorigenicity is unknown. Results We show that neural stem/progenitor cells, but not non-neural embryonic or somatic stem/progenitor cell types, exhibit tumorigenicity and the potential for differentiation into tissue types of all germ layers when they are placed in non-native environment by transplantation into immunodeficient nude mice. Likewise, cancer cells capable of tumor initiation have the property of neural stemness because of their abilities in neurosphere formation in neural stem cell-specific serum-free medium and in differentiation potential, in addition to their neuronal differentiation potential that was characterized previously. Moreover, loss of a pro-differentiation factor in myoblasts, which have no tumorigenicity, lead to the loss of myoblast identity, and gain of the property of neural stemness, tumorigenicity and potential for re-differentiation. These suggest that the property of neural stemness contributes to cell tumorigenicity, and tumor phenotypic heterogeneity might be an effect of differentiation potential of neural stemness. Bioinformatic analysis reveals that neural genes in general are correlated with embryonic development and cancer, in addition to their role in neural development; whereas non-neural genes are not. Most of neural specific genes emerged in typical species representing transition from unicellularity to multicellularity during evolution. Genes in Monosiga brevicollis, a unicellular species that is a closest known relative of metazoans, are biased toward neural cells. Conclusions We suggest that the property of neural stemness is the source of cell tumorigenicity. This is due to that neural biased unicellular state is the ground state for multicellularity and hence cell type diversification or differentiation during evolution, and tumorigenesis is a process of restoration of neural ground state in somatic cells along a default route that is pre-determined by an evolutionary advantage of neural state.

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Section: Immuno Uorescence (If)mentioning

confidence: 99%

Section: Immuno Uorescence (If)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neural stemness contributes to cell tumorigenicity

Zhang

Shi

et al. 2020

Preprint

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“…Previous study suggested that β-catenin can complex with NF-κB, inhibit NF-κB activity and repress its target genes in human colon and breast cancer cells [12]. β-catenin can also complex with HDAC1 to regulate target genes [13]. So β-catenin is probably involved in the FPGS regulation.…”

Section: Introductionmentioning

confidence: 96%

β-catenin promotes MTX resistance of leukemia cells by down-regulating FPGS expression via NF-κB

Liu

Yue

et al. 2020

Cancer Cell Int

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Background: Aberrant activation of β-catenin has been shown to play important roles in the chemoresistance of acute lymphoblastic leukemia (ALL), but the involvement and mechanism of β-catenin in methotrexate (MTX) resistance is poorly understood. In the present study, we demonstrate a critical role of β-catenin-NF-κB-FPGS pathway in MTX resistance in the human T-lineage ALL cell lines. Methods: Lentivirus sh-β-catenin was used to silence the expression of β-catenin. Flow cytometry was performed to detect apoptosis after MTX treatment. Western blot, real-time PCR, Co-immunoprecipitation (Co-IP), Chromatin immunoprecipitation (ChIP), Re-ChIP, and Luciferase assay were utilized to investigate the relationship among β-catenin, nuclear factor (NF)-κB, and folypoly-γ-glutamate synthetase (FPGS). Results: Depletion of β-catenin significantly increased the cytotoxicity of MTX. At the molecular level, knockdown of β-catenin caused the increase of the protein level of FPGS and NF-κB p65. Furthermore, β-catenin complexed with NF-κB p65 and directly bound to the FPGS promoter to regulate its expression. In addition, β-catenin repression prolonged the protein turnover of FPGS. Conclusions: Taken together, our results demonstrate that β-catenin may contribute to MTX resistance in leukemia cells via the β-catenin-NF-κB-FPGS pathway, posing β-catenin as a potential target for combination treatments during ALL therapy.

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EZH2 is a key component of hepatoblastoma tumor cell growth

Glaser,

Schepers,

Zwolshen

et al. 2023

Pediatric Blood & Cancer

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BackgroundEnhancer of zeste homolog 2 (EZH2) catalyzes the trimethylation of histone H3 at lysine 27 via the polycomb recessive complex 2 (PRC2) and plays a time‐specific role in normal fetal liver development. EZH2 is overexpressed in hepatoblastoma (HB), an embryonal tumor. EZH2 can also promote tumorigenesis via a noncanonical, PRC2‐independent mechanism via proto‐oncogenic, direct protein interaction, including β‐catenin. We hypothesize that the pathological activation of EZH2 contributes to HB propagation in a PRC2‐independent manner.Methods and resultsWe demonstrate that EZH2 promotes proliferation in HB tumor‐derived cell lines through interaction with β‐catenin. Although aberrant EZH2 expression occurs, we determine that both canonical and noncanonical EZH2 signaling occurs based on specific gene‐expression patterns and interaction with SUZ12, a PRC2 component, and β‐catenin. Silencing and inhibition of EZH2 reduce primary HB cell proliferation.ConclusionsEZH2 overexpression promotes HB cell proliferation, with both canonical and noncanonical function detected. However, because EZH2 directly interacts with β‐catenin in human tumors and EZH2 overexpression is not equal to SUZ12, it seems that a noncanonical mechanism is contributing to HB pathogenesis. Further mechanistic studies are necessary to elucidate potential pathogenic downstream mechanisms and translational potential of EZH2 inhibitors for the treatment of HB.

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EZH2 Regulates Protein Stability via Recruiting USP7 to Mediate Neuronal Gene Expression in Cancer Cells

Cited by 34 publications

References 58 publications

Neural stemness contributes to cell tumorigenicity

Neural stemness contributes to cell tumorigenicity

β-catenin promotes MTX resistance of leukemia cells by down-regulating FPGS expression via NF-κB

EZH2 is a key component of hepatoblastoma tumor cell growth

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