EZH2 blockade by RNA interference inhibits growth of ovarian cancer by facilitating re-expression of p21waf1/cip1 and by inhibiting mutant p53

Seward, Shelly; Semaan, Assaad; Qazi, Aamer; Gruzdyn, Oksana V.; Chamala, Sreedhar; Bryant, Christopher C.; Kumar, Sanjeev; Cameron, David; Sethi, Seema; Ali-Fehmi, Rouba; Morris, Robert T.; Bouwman, David L.; Munkarah, Adnan; Weaver, Donald W.; Gruber, Scott A.; Batchu, Ramesh B.

doi:10.1016/j.canlet.2013.04.012

Cited by 27 publications

(21 citation statements)

References 31 publications

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“…S1E). There are evidence that showed that EZH2 could regulate KLF2 and P21 expression (20,21), and our qPCR results also showed that inhibition of ANRIL expression led to increased KLF2 and P21 expression. Moreover, knockdown of EZH2 or SUZ12 could also upregulate KLF2 and P21 expression (Fig.…”

Section: Anril Silences Klf2 and P21 Transcription By Binding With Ezh2supporting

confidence: 64%

Long Noncoding RNA ANRIL Promotes Non–Small Cell Lung Cancer Cell Proliferation and Inhibits Apoptosis by Silencing KLF2 and P21 Expression

Nie

Sun

Yang

et al. 2015

Molecular Cancer Therapeutics

336

294

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Recent evidence highlights long noncoding RNAs (lncRNA) as crucial regulators of cancer biology that contribute to essential cancer cell functions such as cell proliferation, apoptosis, and metastasis. In non-small cell lung cancer (NSCLC), several lncRNAs' expressions are misregulated and have been nominated as critical actors in NSCLC tumorigenesis. LncRNA ANRIL was first found to be required for the PRC2 recruitment to and silencing of p15 INK4B , the expression of which is induced by the ATM-E2F1 signaling pathway. Our previous study showed that ANRIL was significantly upregulated in gastric cancer, and it could promote cell proliferation and inhibit cell apoptosis by silencing of miR99a and miR449a transcription. However, its clinical significance and potential role in NSCLC is still not documented. In this study, we reported that ANRIL expression was increased in NSCLC tissues, and its expression level was significantly correlated with tumor-node-metastasis stages and tumor size. Moreover, patients with high levels of ANRIL expression had a relatively poor prognosis. In addition, taking advantage of loss-of-function experiments in NSCLC cells, we found that knockdown of ANRIL expression could impair cell proliferation and induce cell apoptosis both in vitro and vivo. Furthermore, we uncover that ANRIL could not repress p15 expression in PC9 cells, but through silencing of KLF2 and P21 transcription. Thus, we conclusively demonstrate that lncRNA ANRIL plays a key role in NSCLC development by associating its expression with survival in patients with NSCLC, providing novel insights on the function of lncRNA-driven tumorigenesis.

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Section: Anril Silences Klf2 and P21 Transcription By Binding With Ezh2supporting

confidence: 64%

Long Noncoding RNA ANRIL Promotes Non–Small Cell Lung Cancer Cell Proliferation and Inhibits Apoptosis by Silencing KLF2 and P21 Expression

Nie

Sun

Yang

et al. 2015

Molecular Cancer Therapeutics

336

294

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“…Despite strong down-regulation of H3K27me3, proliferation was unimpaired. Prior studies suggest that Ezh2 can control cell proliferation in part through silencing of the Ink4a/Arf and p21 tumor suppressor loci (Bracken et al 2007;Seward et al 2013). However, the levels of p16/p19 transcripts, already detectable in sh-scramble Myc-CaP cells, were not affected upon Ezh2 knockdown in this model ( Fig.…”

Section: Resultsmentioning

confidence: 55%

Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis

Wassef¹,

Rodilla²,

Teissandier³

et al. 2015

Genes Dev.

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Alterations of chromatin modifiers are frequent in cancer, but their functional consequences often remain unclear. Focusing on the Polycomb protein EZH2 that deposits the H3K27me3 (trimethylation of Lys27 of histone H3) mark, we showed that its high expression in solid tumors is a consequence, not a cause, of tumorigenesis. In mouse and human models, EZH2 is dispensable for prostate cancer development and restrains breast tumorigenesis. High EZH2 expression in tumors results from a tight coupling to proliferation to ensure H3K27me3 homeostasis. However, this process malfunctions in breast cancer. Low EZH2 expression relative to proliferation and mutations in Polycomb genes actually indicate poor prognosis and occur in metastases. We show that while altered EZH2 activity consistently modulates a subset of its target genes, it promotes a wider transcriptional instability. Importantly, transcriptional changes that are consequences of EZH2 loss are predominantly irreversible. Our study provides an unexpected understanding of EZH2's contribution to solid tumors with important therapeutic implications.

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“…Some other studies have also previously demonstrated the effect of EZH2 silencing on cisplatin-resistant ovarian cancer cells. 6,7 These findings present EZH2 as a new candidate that could possibly reverse the cisplatin resistance of ovarian cancer cells.…”

Section: Discussionmentioning

confidence: 95%

“…4,5 Some studies have previously demonstrated that EZH2 is essential for chemotherapy resistance in cisplatin-resistant cancer cells and EZH2 knockdown can enhance chemosensitivity. 6,7 However, whether EZH2 can reverse the cisplatin resistance of ovarian cancer is unclear. This study aimed to determine the effects of EZH2 on cisplatin resistance through RNA interference to further explore the underlying mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Interfering EZH2 Expression Reverses the Cisplatin Resistance in Human Ovarian Cancer by Inhibiting Autophagy

Sun

Jin

Liu

et al. 2016

Cancer Biotherapy and Radiopharmaceuticals

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We aimed to determine the effects of the inhibition of enhancer of zeste homolog 2 (EZH2) gene expression on the cisplatin resistance of the human ovarian cancer cell line, SKOV3/DDP, and to identify the underlying mechanisms. SKOV3/DDP cells were stably transfected with pSUPER-EZH2 (EZH2 RNA interference plasmid) or pcDNA3.1-EZH2 (EZH2 gene overexpression plasmid) using the lipofection method. Real-time fluorescence quantitative reverse transcription polymerase chain reaction and western blotting confirmed that EZH2 expression was downregulated in pSUPER-EZH2-transfected cells. Flow cytometry revealed that EZH2 inhibition did not induce apoptosis, but significantly inhibited autophagy. In addition, it significantly increased the expression of the cellular senescence-signaling proteins p14(ARF), p16(INK4a), p53, pRb, and p21, and significantly decreased the expression of cyclin-dependent kinase (CDK)1, CDK2, and H3K27me3. Cellular senescence was characterized by a significant increase in the G0/G1 ratio and the restoration of sensitivity to cisplatin in the drug-resistant cells. These findings suggest that interfering with EZH2 expression can inhibit SKOV3/DDP cell autophagy and reverse resistance to cisplatin. The underlying mechanisms could be associated with the regulation of the cellular senescence-signaling pathway.

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EZH2 blockade by RNA interference inhibits growth of ovarian cancer by facilitating re-expression of p21waf1/cip1 and by inhibiting mutant p53

Cited by 27 publications

References 31 publications

Long Noncoding RNA ANRIL Promotes Non–Small Cell Lung Cancer Cell Proliferation and Inhibits Apoptosis by Silencing KLF2 and P21 Expression

Long Noncoding RNA ANRIL Promotes Non–Small Cell Lung Cancer Cell Proliferation and Inhibits Apoptosis by Silencing KLF2 and P21 Expression

Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis

Interfering EZH2 Expression Reverses the Cisplatin Resistance in Human Ovarian Cancer by Inhibiting Autophagy

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