Role of EZH2 in cancer stem cells: from biological insight to a therapeutic target

Wen, Yiping; Cai, Jing; Hou, Yaya; Huang, Zaiju; Wang, Zehua

doi:10.18632/oncotarget.16467

Cited by 67 publications

(56 citation statements)

References 133 publications

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“…Our previous study found that hnRNPK regulates diverse functions in bladder cancer by directly mediating transcription of target genes; however, the detailed mechanism remained unclear (24). EZH2, a histone methyl transferase subunit of the polycomb repressor complex 2 (PRC2), is an oncogene that is central to tumor proliferation, metastasis, and self-renewal (40,41). In the present study, we found that lnc-LBCS physically interacts with hnRNPK and EZH2, and lnc-LBCS serves as a scaffold to induce the formation of hnRNPK-EZH2 complex.…”

Section: Discussionmentioning

confidence: 99%

Long Noncoding RNA LBCS Inhibits Self-Renewal and Chemoresistance of Bladder Cancer Stem Cells through Epigenetic Silencing of SOX2

Chen

Xie

et al. 2019

Clinical Cancer Research

176

140

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Purpose: Chemoresistance and tumor relapse are the leading cause of deaths in bladder cancer patients. Bladder cancer stem cells (BCSCs) have been reported to contribute to these pathologic properties. However, the molecular mechanisms underlying their self-renewal and chemoresistance remain largely unknown. In the current study, a novel lncRNA termed Low expressed in Bladder Cancer Stem cells (lnc-LBCS) has been identified and explored in BCSCs.Experimental Design: Firstly, we establish BCSCs model and explore the BCSCs-associated lncRNAs by transcriptome microarray. The expression and clinical features of lnc-LBCS are analyzed in three independent large-scale cohorts. The functional role and mechanism of lnc-LBCS are further investigated by gain-and loss-of-function assays in vitro and in vivo.Results: Lnc-LBCS is significantly downregulated in BCSCs and cancer tissues, and correlates with tumor grade, chemo-therapy response, and prognosis. Moreover, lnc-LBCS markedly inhibits self-renewal, chemoresistance, and tumor initiation of BCSCs both in vitro and in vivo. Mechanistically, lnc-LBCS directly binds to heterogeneous nuclear ribonucleoprotein K (hnRNPK) and enhancer of zeste homolog 2 (EZH2), and serves as a scaffold to induce the formation of this complex to repress SRY-box 2 (SOX2) transcription via mediating histone H3 lysine 27 tri-methylation. SOX2 is essential for self-renewal and chemoresistance of BCSCs, and correlates with the clinical severity and prognosis of bladder cancer patients.Conclusions: As a novel regulator, lnc-LBCS plays an important tumor-suppressor role in BCSCs' self-renewal and chemoresistance, contributing to weak tumorigenesis and enhanced chemosensitivity. The lnc-LBCS-hnRNPK-EZH2-SOX2 regulatory axis may represent a therapeutic target for clinical intervention in chemoresistant bladder cancer.

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Section: Discussionmentioning

confidence: 99%

Long Noncoding RNA LBCS Inhibits Self-Renewal and Chemoresistance of Bladder Cancer Stem Cells through Epigenetic Silencing of SOX2

Chen

Xie

et al. 2019

Clinical Cancer Research

176

140

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“…EZH2 is upregulated in many cancers and its enhanced expression of EZH2 is associated with invasion, migration and stemness (Yamaguchi and Hung 2014). In breast cancer, overexpression of EZH2 has increased mammosphere formation and self-renewal ability in breast CSCs (Chang, Yang et al 2011, Wen, Cai et al 2017. In glioblastoma, loss of H3K27me3 leads to aberrant activation of a transcription factor, ASCL1 and results in Wnt activation which is required for tumorigenicity and CSC maintenance (Rheinbay, Suva et al 2013).…”

Section: Mechanisms Controlling Csc Plasticitymentioning

confidence: 99%

Cancer Stem Cell Plasticity – A Deadly Deal

Archana¹,

Kritika²,

Murali³

et al. 2019

Preprint

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Intratumoral heterogeneity is a major ongoing challenge in the effective therapeutic targeting of cancer. Accumulating evidence suggests that a fraction of cells within a tumor termed Cancer Stem Cells (CSCs) are primarily responsible for this diversity resulting in therapeutic resistance and metastasis. Adding to this complexity, recent studies have shown that there can be different subpopulations of CSCs with varying biochemical and biophysical traits resulting in varied dissemination and drug-resistance potential. Moreover, cancer cells can exhibit a high level of plasticity or the ability to dynamically switch between CSC and non-CSC states or among different subsets of CSCs. The molecular mechanisms underlying such plasticity has been under extensive investigation and the trans-differentiation process of Epithelial to Mesenchymal transition (EMT) has been identified as a major contributing factor. Besides genetic and epigenetic factors, CSC plasticity is also shaped by non-cell-autonomous effects such as the tumor microenvironment. In this review, we discuss the recent developments in understanding CSC plasticity in tumor progression at biochemical and biophysical levels, and the latest in silico approaches being taken for characterizing cancer cell plasticity with implications in improving existing therapeutic approaches.

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“…Ezh2 belongs to the polycomb repressive complex 2 (PRC2), which participates in methylation of histone 3 (H3K27me) leading to transcriptional repression (33,34). Ezh2 has been described to have an important role in coordinating cell differentiation in embryonic stem cells (35,36), mesenchymal stem cells (37-39), hematopoietic stem cells (40,41), and also in various types of cancer (42,43). Inhibition of Ezh2 has been reported to prevent renal fibroblast activation (44), though more recently the same group reported that Ezh2 acts in epithelial cells to promote fibrosis (45).…”

Section: Differential Expression Of Transcription Factors and Secretementioning

confidence: 99%

FoxM1 drives proximal tubule proliferation during repair from acute kidney injury

Chang-Panesso

Kadyrov

Lalli

et al. 2018

Preprint

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word count: 157 Text word count: 8,552 AbstractThe proximal tubule has a remarkable capacity for repair after acute injury but the cellular lineage and molecular mechanisms underlying this repair response have been poorly characterized. Here, we developed a Kim-1-GFPCreER t2 knockin mouse line (Kim-1-GCE), performed genetic lineage analysis after injury and measured the cellular transcriptome of proximal tubule during repair. Acutely injured genetically labeled clones co-expressed Kim-1, Vimentin, Sox9 and Ki67, indicating a dedifferentiated and proliferative state. Clonal analysis revealed clonal expansion of Kim-1+ cells, indicating that acutely injured, dedifferentiated proximal tubule cells account for repair rather than a fixed tubular progenitor. Translational profiling during injury and repair revealed signatures of both successful and unsuccessful maladaptive repair. The transcription factor FoxM1 was induced early in injury, was required for epithelial proliferation, and was dependent on epidermal growth factor receptor (EGFR) stimulation. In conclusion, dedifferentiated proximal tubule cells effect proximal tubule repair and we reveal a novel EGFR-FoxM1-dependent signaling pathway that drives proliferative repair after injury. IntroductionAcute kidney injury (AKI) has a wide spectrum of outcomes ranging from full recovery to failed repair and transition to chronic kidney disease. According to a recent report from the CDC examining trends in hospitalizations for acute kidney injury in the US from 2000 to 2014, the rate of AKI hospitalizations increased by 230% over this time frame, going from 3.5 to 11.7 per 1000 persons (1). Furthermore, it has been reported that Medicare patients aged 66 years and older who were hospitalized for AKI had a 35% cumulative probability of a recurrent AKI hospitalization within one year and 28% were diagnosed as having CKD in the year following an AKI hospitalization (2). These troubling statistics points toward a pressing need to identify therapeutic interventions to prevent and treat AKI.The proximal tubular epithelium makes up the bulk of the kidney cortex and is responsible for reabsorption of a large portion of the glomerular filtered load in order to maintain solute and volume homeostasis. Due to its high metabolic activity, it is also the renal compartment more vulnerable to injury. It is well known that the tubular epithelium has regenerative potential; however, this repair capacity is not unlimited and may be dependent on the degree of injury (3). Based on studies from our lab and others, acute injury with proximal tubule death is followed by a wave of tubular proliferation, peaking at 48 hours after injury, to restore tubular cell mass. Lineage analysis indicates that the source of the repairing cells derives from within the tubule rather than a circulating or interstitial progenitor (4). Several lines of evidence indicate that surviving epithelia dedifferentiate, and these dedifferentiated epithelia have an equivalent capacity for repair (5)(6)(7)(8). By contrast...

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Role of EZH2 in cancer stem cells: from biological insight to a therapeutic target

Cited by 67 publications

References 133 publications

Long Noncoding RNA LBCS Inhibits Self-Renewal and Chemoresistance of Bladder Cancer Stem Cells through Epigenetic Silencing of SOX2

Long Noncoding RNA LBCS Inhibits Self-Renewal and Chemoresistance of Bladder Cancer Stem Cells through Epigenetic Silencing of SOX2

Cancer Stem Cell Plasticity – A Deadly Deal

FoxM1 drives proximal tubule proliferation during repair from acute kidney injury

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Role of EZH2 in cancer stem cells: from biological insight to a therapeutic target

Cited by 67 publications

References 133 publications

Long Noncoding RNA LBCS Inhibits Self-Renewal and Chemoresistance of Bladder Cancer Stem Cells through Epigenetic Silencing of SOX2

Long Noncoding RNA LBCS Inhibits Self-Renewal and Chemoresistance of Bladder Cancer Stem Cells through Epigenetic Silencing of SOX2

Cancer Stem Cell Plasticity &ndash; A Deadly Deal

FoxM1 drives proximal tubule proliferation during repair from acute kidney injury

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Cancer Stem Cell Plasticity – A Deadly Deal