Mutation Spectra of Histone Methyltransferases With Canonical SET Domains and EZH2-Targeted Therapy

Katoh, Masaru

doi:10.2217/epi.15.89

Cited by 29 publications

(28 citation statements)

References 143 publications

(232 reference statements)

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“…Thus, more research should be undertaken to get a better understanding of epigenetic mechanisms and the influence of EZH2 targeted agents on potential survival benefit in CRC patients, which may promote a novel clinical strategy for CRC treatment. Meanwhile, a variety of inhibitors suppress the EZH2 via different mechanisms, such as regulation of other targets or signal pathways, competing toward the SET domain of EZH2 and inducing relevant protein degradation [43,44,45]. All methods of inhibiting EZH2 seem have a potential benefit for treating solid tumors [45,46,47,48].…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Enhancer of Zeste Homolog 2 (EZH2) is essential for the Induction of Autophagy and Apoptosis in Colorectal Cancer Cells

Yao

Yang

et al. 2016

Genes

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Increasing evidence indicates that elevated expression of enhancer of zeste homolog 2 gene (EZH2) in many human malignant tumors acts a significant role in the oncogenic process. However, the underlying molecular mechanism is still unclarified. It is evident that apoptosis and autophagy of tumor cells is crucial for the tumorigenesis and progression of cancer, however, the exact role of EZH2 plays in apoptosis and autophagy has not been fully elucidated in colorectal cancer (CRC). Our previous study found that the expression level of EZH2 was higher in CRC tumor tissues than in the paired normal tissues using immunohistochemical analysis. We also recently found that the autophagy-related gene-related protein Ambra1 plays an important role in the autophagy pathway in CRC cells. In this study, mRNA and protein expression of EZH2 in four CRC cell lines were tested at first and RKO and HCT116 cells showed the highest levels among them. Here we transfected with EZH2-shRNA, or added DZNep (an EZH2 inhibitor) to RKO and HCT116 cells in order to detect the effect of EZH2 on autophagy via determining the change of the protein expression of LC3 and Ambra1. The outcome indicated an obvious decrease of autophagy level in cells transfected with EZH2-shRNA or DZNep. We also found the apoptotic rate of cells was elevated significantly after downregulation of EZH2. In addition, compared to control group, CRC cells transfected with EZH2-shRNA or added DZNep revealed a significantly increased G1 cell cycle rate and an obvious decrease in the G2 cell cycle rate. Further analysis showed that knockdown of EZH2 induced cell-cycle arrest in CRC cells. Meanwhile, downregulation of EZH2 in CRC cells induces autophagy and apoptosis. Taken together, our results suggest that EZH2 plays a critical role in autophagy and apoptosis in the progression of CRC, which potentially facilitates the development of an ideal strategy for combating colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

Downregulation of Enhancer of Zeste Homolog 2 (EZH2) is essential for the Induction of Autophagy and Apoptosis in Colorectal Cancer Cells

Yao

Yang

et al. 2016

Genes

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“…β-catenin, encoded by the CTNNB1 gene, is a scaffold protein that interacts with WNT signaling components (including APC, AXIN, BCL9 and TCF/LEF), adhesion molecules (such as E-cadherin, N-cadherin and α-catenin) and epigenetic/transcriptional regulators (for example, CBP, p300, EZH2 and SMARCA4/BRG1) (43,44). Cadherin-bound β-catenin is stable and involved in the maintenance of cell-cell adhesion, whereas cytoplasmic free β-catenin is degraded in the proteasome through priming phosphorylation at S45 by CK1, following phosphorylation at S33, S37 and T41 by GSK3β, and subsequent poly-ubiquitylation at K19 by E3 ubiquitin ligase (45).…”

Section: Intellectual Disability Syndrome Alzheimer's Disease Andmentioning

confidence: 99%

Molecular genetics and targeted therapy of WNT-related human diseases (Review)

Katoh¹,

2017

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Canonical WNT signaling through Frizzled and LRP5/6 receptors is transduced to the WNT/β-catenin and WNT/stabilization of proteins (STOP) signaling cascades to regulate cell fate and proliferation, whereas non-canonical WNT signaling through Frizzled or ROR receptors is transduced to the WNT/planar cell polarity (PCP), WNT/G protein-coupled receptor (GPCR) and WNT/receptor tyrosine kinase (RTK) signaling cascades to regulate cytoskeletal dynamics and directional cell movement. WNT/β-catenin signaling cascade crosstalks with RTK/SRK and GPCR-cAMP-PKA signaling cascades to regulate β-catenin phosphorylation and β-catenin-dependent transcription. Germline mutations in WNT signaling molecules cause hereditary colorectal cancer, bone diseases, exudative vitreoretinopathy, intellectual disability syndrome and PCP-related diseases. APC or CTNNB1 mutations in colorectal, endometrial and prostate cancers activate the WNT/β-catenin signaling cascade. RNF43, ZNRF3, RSPO2 or RSPO3 alterations in breast, colorectal, gastric, pancreatic and other cancers activate the WNT/β-catenin, WNT/STOP and other WNT signaling cascades. ROR1 upregulation in B-cell leukemia and solid tumors and ROR2 upregulation in melanoma induce invasion, metastasis and therapeutic resistance through Rho-ROCK, Rac-JNK, PI3K-AKT and YAP signaling activation. WNT signaling in cancer, stromal and immune cells dynamically orchestrate immune evasion and antitumor immunity in a cell context-dependent manner. Porcupine (PORCN), RSPO3, WNT2B, FZD5, FZD10, ROR1, tankyrase and β-catenin are targets of anti-WNT signaling therapy, and ETC-159, LGK974, OMP-18R5 (vantictumab), OMP-54F28 (ipafricept), OMP-131R10 (rosmantuzumab), PRI-724 and UC-961 (cirmtuzumab) are in clinical trials for cancer patients. Different classes of anti-WNT signaling therapeutics are necessary for the treatment of APC/CTNNB1-, RNF43/ZNRF3/RSPO2/RSPO3- and ROR1-types of human cancers. By contrast, Dickkopf-related protein 1 (DKK1), SOST and glycogen synthase kinase 3β (GSK3β) are targets of pro-WNT signaling therapy, and anti-DKK1 (BHQ880 and DKN-01) and anti-SOST (blosozumab, BPS804 and romosozumab) monoclonal antibodies are being tested in clinical trials for cancer patients and osteoporotic post-menopausal women. WNT-targeting therapeutics have also been applied as reagents for in vitro stem-cell processing in the field of regenerative medicine.

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“…EZH2 is frequently overexpressed and considered to be an oncogene in cancers (49). The SET domain of EZH2 possesses methyltransferase activity specific for histone H3K27 (50, 51). The role of deregulated PRC2 in tumor suppressor gene expression, DNA damage response, and the fidelity of DNA replication has been suggested (52), resulting in long-term reversible suppression p14 ARF and p16 INK4a .…”

Section: Prc (Polycomb Repressor Complex) Mediated Inhibition Of P16imentioning

confidence: 99%

Aberrant expression of p16INK4a in human cancers – a new biomarker?

Inoue

Fry

2018

Cancer Rep Rev

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The ARF and INK4a genes are located in the same CDKN2a locus, both showing its tumor suppressive activity. ARF has been shown to detect potentially harmful oncogenic signals, making incipient cancer cells undergo senescence or apoptosis. INK4a, on the other hand, responds to signals from aging in a variety of tissues including islets of Langerhans, neuronal cells, and cancer stem cells in general. It also detects oncogenic signals from incipient cancer cells to induce them senescent to prevent neoplastic transformation. Both of these genes are inactivated by gene deletion, promoter methylation, frame shift, and aberrant splicing although mutations changing the amino acid sequences affect only the latter. Recent studies indicated that polycomb gene products EZH2 and BMI1 repressed p16INK4a expression in primary cells, but not in cells deficient for pRB protein function. It was also reported that that p14ARF inhibits the stability of the p16INK4a protein in human cancer cell lines and mouse embryonic fibroblasts through its interaction with regenerating islet-derived protein 3γ. Overexpression of INK4a is associated with better prognosis of cancer when it is associated with human papilloma virus infection. However, it has a worse prognostic value in other tumors since it is an indicator of pRB loss. The p16INK4a tumor suppressive protein can thus be used as a biomarker to detect early stage cancer cells as well as advanced tumor cells with pRB inactivation since it is not expressed in normal cells.

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Mutation Spectra of Histone Methyltransferases With Canonical SET Domains and EZH2-Targeted Therapy

Cited by 29 publications

References 143 publications

Downregulation of Enhancer of Zeste Homolog 2 (EZH2) is essential for the Induction of Autophagy and Apoptosis in Colorectal Cancer Cells

Downregulation of Enhancer of Zeste Homolog 2 (EZH2) is essential for the Induction of Autophagy and Apoptosis in Colorectal Cancer Cells

Molecular genetics and targeted therapy of WNT-related human diseases (Review)

Aberrant expression of p16INK4a in human cancers – a new biomarker?

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