DZNep inhibits the proliferation of colon cancer HCT116 cells by inducing senescence and apoptosis

Sha, Ming-Quan; Mao, Genxiang; Wang, Guofu; Chen, Yufeng; Wu, Xiaojian; Wang, Zhen

doi:10.1016/j.apsb.2015.01.011

Cited by 24 publications

(25 citation statements)

References 25 publications

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“…Targeting EZH2 can be an effective therapeutic strategy for colon cancer. Sha et al demonstrated that DZNep can inhibit the growth and survival of colon cancer HCT116 cells by inducing cellular senescence and apoptosis (9). This study is also consistent with our results in which DZNep showed a toxic activity on HT-29 cell line.…”

Section: Resultssupporting

confidence: 93%

“…3-Deazaneplanocin A (DZNep) is an S-adenosylhomocysteine synthesis and histone methyltransferase EZH2 inhibitor that has a wide range of effects in various human cancers. In recent studies, DZNep has also been shown to have an impact on apoptosis in CRC cell cultures (9). However, the relationship of AP-related genes in DZNep-treated CRC cells remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

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DZNep Does Not Influence Autophagy Gene Expression in the Colon Cancer Cell Line HT-29

Koca¹,

Akinci²,

Ünal³

et al. 2019

Akd Med J

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Objective: Autophagy (AP) is a well-preserved cell survival mechanism that plays a critical role by degrading dysfunctional organelles and misfolded proteins. There are a limited number of studies examining the relationship between 3-Deazaneplanocin A hydrochloride (DZNep) and autophagy. The purpose of this preliminary study was to assess the effect of DZNep on the expression of the APrelated genes Beclin-1, Ulk1, Ulk2 and Uvrag in HT-29 colorectal adenocarcinoma cells. Material and Methods: HT-29 human colorectal adenocarcinoma cells were plated into growth medium. The next day, 25 µM DZNep, an inhibitor of S-Adenosylmethionine-dependent methyltransferase, was added to the cells. DZNep were removed from the cells after 4 days by refreshing the media. The cells were maintained in a tissue culture incubator. Total RNA isolation was performed from DZNep treated and untreated HT-29 cells 4 days after DZNep application. cDNAs were reverse transcribed from 2 µg of DNase treated RNA. cDNAs were then analyzed by quantitative PCR. The results were presented as relative expression level in HT-29 cells. Results: DZNep induced extreme cell death on HT-29 colorectal cancer cell lines; more than 50% of the colorectal cancer cells were dead. The expression level of Beclin-1 was the smallest while Ulk1 and Uvrag expression levels were higher than that of Beclin-1, and Ulk2 had the highest expression level in untreated HT-29 colorectal cancer lines. Conclusion: The autophagy related genes studied here consisting of Beclin-1, Ulk1, Ulk2, and Uvrag were not affected by DZNep application. Based on mRNA expression levels of AP genes, administration of DZNep does not stimulate cell toxicity through autophagy in the HT-29 cells.

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Section: Resultssupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

DZNep Does Not Influence Autophagy Gene Expression in the Colon Cancer Cell Line HT-29

Koca¹,

Akinci²,

Ünal³

et al. 2019

Akd Med J

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“…Abnormal proliferation is a common feature of malignant tumors. DZNep has been confirmed to be able to inhibit the proliferation of Eca109 oesophageal squamous cell carcinoma cells and HTC116 colorectal cancer cells (25,26). The present study used the poorly differentiated human BGC-823 gastric adenocarcinoma cell line.…”

Section: Discussionmentioning

confidence: 96%

DZNep inhibits Hif‑1α and Wnt signalling molecules to attenuate the proliferation and invasion of BGC‑823 gastric cancer cells

et al. 2019

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3-deazaneplanocin A (DZNep) is a histone methyltransferase inhibitor, which may cause the reactivation of silenced tumor suppressor genes in tumors to inhibit the development, metastasis and dissemination of tumor cells. However, the effects and mechanisms of its application in gastric cancer remain unclear. The present study revealed an inhibitory function of DZNep in BGC-823 cells. The cell colony, Cell Counting Kit-8 (CCK8), wound healing, Transwell and flow cytometry assays were performed, and the results demonstrated that DZNep could inhibit the proliferation, apoptosis and invasion of BGC-823 cells, and promote their apoptosis. The effects of intervention in BDC-823 cells with DZNep on the RNA and protein expression levels of hypoxia-inducible factor (Hif-1α) and Wnt/β-catenin signalling molecules were further examined using reverse transcription-quantitative PCR and western blot analysis. The results demonstrated that different concentrations of DZNep could inhibit the expression of enhancer of zeste homolog 2 (EZH2) protein, decrease the RNA and protein expression levels of Hif-1α, total β-catenin and phosphorylated-β-catenin and increase the expression levels of non-phosphorylated-β-catenin to different degrees. The results of the present study suggests that DZNep inhibits BGC-823 gastric cancer cells via the inhibition of EZH2, Hif-1α and Wnt/β-catenin signalling molecules. These results provide theoretical basis for the application of DZNep in clinical trials.

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“…16, 34 Our previous work also proved the senescence-inducing ability of an EZH2 inhibitor DZNep in HCT116 cells. 35 Although p16 induction is not observed, p21 is indeed regulated by EZH2 and contributes substantially to senescence induction after DZNep or LDM treatment. Meanwhile, the p21 induction by LDM occurs independently of p53.…”

Section: Discussionmentioning

confidence: 95%

EZH2 mediates lidamycin-induced cellular senescence through regulating p21 expression in human colon cancer cells

et al. 2016

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Lidamycin (LDM) is a novel member of the enediyne antibiotics identified in China with potent antitumor activity. However, it remains unclear whether LDM has potential molecular targets that may affect its antitumor activity. Enhancer of zeste homolog 2 (EZH2) functions as a histone lysine methyltransferase and mediates trimethylation on histone 3 lysine 27 (H3K27me3). High EZH2 level is found to be positively correlated with the aggressiveness, metastasis and poor prognosis of cancer. Here, we aim to study the role of EZH2 in LDM-induced senescence, as well as in the cytotoxicity of LDM in human colon cancer cells. LDM is found to be relatively more potent in inhibiting the colon cancer cells harboring high EZH2 level and induces irreversible cellular senescence at IC50 dose range, as evidenced by senescence-associated β-galactosidase staining, cell cycle arrest and molecular changes of senescence regulators including p21 in HCT116 and SW620 cells. More importantly, LDM is found to markedly inhibit EZH2 expression at both protein and mRNA levels upon the induction of p21 and cellular senescence. LDM also selectively inhibits EZH2 expression as compared with other histone lysine methyltransferases. Knockdown of p21 with siRNAs abolishes LDM-induced senescence, whereas EZH2 knockdown markedly increases p21 expression and causes senescent phenotype. Enrichment of both EZH2 and H3K27me3 levels in the p21 promoter region is reduced by LDM. Moreover, EZH2 overexpression reduces cellular senescence, p21 expression and DNA damage response upon LDM exposure. LDM also demonstrates potent antitumor efficacy in xenografted animal models. Collectively, our work provides first demonstration that EZH2 may mediate, at least partially, the senescence-inducing effects of LDM by regulating p21 expression and DNA damage effect. Thus, EZH2 may serve as a potential target and biomarker to indicate the clinical efficacy of the potent enediyne antitumor drug.

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DZNep inhibits the proliferation of colon cancer HCT116 cells by inducing senescence and apoptosis

Cited by 24 publications

References 25 publications

DZNep Does Not Influence Autophagy Gene Expression in the Colon Cancer Cell Line HT-29

DZNep Does Not Influence Autophagy Gene Expression in the Colon Cancer Cell Line HT-29

DZNep inhibits Hif‑1α and Wnt signalling molecules to attenuate the proliferation and invasion of BGC‑823 gastric cancer cells

EZH2 mediates lidamycin-induced cellular senescence through regulating p21 expression in human colon cancer cells

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