HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer

Mahara, Sylvia; Lee, Puay Leng; Feng, Min; Tergaonkar, Vinay; Chng, Wee Joo; Q, Yu

doi:10.1073/pnas.1602079113

Cited by 73 publications

(67 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Chang et al (33) reported that in breast tumor initiating cells (BTICs), the transactivation function mediated by Hif-1α significantly upregulates EZH2 expression, whereas high EZH2 expression causes BTIC proliferation and promotes their progression. The conserved HRE sequence that interacts with Hif-1α was identified in the promoter region of EZH2, which confirmed that hypoxia induces Hif-1α to bind to this HRE region to activate EZH2 transcription, and to promote breast cancer growth (34). DZNep was the first discovered inhibitor of the enzyme activity of EZH2.…”

Section: Discussionmentioning

confidence: 64%

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

et al. 2019

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 64%

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

et al. 2019

View full text Add to dashboard Cite

show abstract

“…The present study also demonstrates major roles for both HIF1␣ and TWIST1 in TNBC tumor maintenance/growth (HIF1␣) and metastasis (TWIST1). To date, the literature on the role of TWIST1 and HIF1␣ in TNBC has been limited, with HIF1␣ even playing a paradoxical role as a modifier of the tumor suppressing function of PRC2 (17)(18)(19). In this study, a major role was identified for TWIST1 in both the AnR and downstream metastasis of TNBC, as down-regulation of this DNA trans-factor led to significant loss of AnR and, subsequently, a reduction in the metastatic rate enhanced by CPEB2B expression.…”

Section: Cpeb2 Rna Splicing Regulates Emt and Hypoxic Responsesmentioning

confidence: 73%

Splice variants of cytosolic polyadenylation element–binding protein 2 (CPEB2) differentially regulate pathways linked to cancer metastasis

DeLigio¹,

Lin²,

Chalfant

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

The translational regulator cytosolic polyadenylation element-binding protein 2 (CPEB2) has two isoforms, CPEB2A and CPEB2B, derived by alternative splicing of RNA into a mature form that either includes or excludes exon 4. Previously, we reported that this splicing event is highly dysregulated in aggressive forms of breast cancers, which overexpress CPEB2B. The loss of CPEB2A with a concomitant increase in CPEB2B was also required for breast cancer cells to resist cell death because of detachment (anoikis resistance) and metastasize To examine the mechanism by which CPEB2 isoforms mediate opposing effects on cancer-related phenotypes, we used next generation sequencing of triple negative breast cancer cells in which the isoforms were specifically down-regulated. Down-regulation of the CPEB2B isoform inhibited pathways driving the epithelial-to-mesenchymal transition and hypoxic response, whereas down-regulation of the CPEB2A isoform did not have this effect. Examining key nodes of these pathways showed that CPEB2B induced the expression of regulatory DNA-factors ( HIF1α and TWIST1). Specifically, CPEB2B functioned as a translational activator of TWIST1 and HIF1α. Functional studies showed that specific down-regulation of either HIF1α or TWIST1 inhibited the ability of CPEB2B to induce the acquisition of anoikis resistance and drive metastasis. Overall, this study demonstrates that CPEB2 alternative splicing is a major regulator of key cellular pathways linked to anoikis resistance and metastasis.

show abstract

“…Enhancer of zeste homologue 2 (EZH2), as a histone methyltransferase, is a catalytic subunit of polycomb repressive complex 2 (PRC2) which induces transcriptional inhibition through the tri-methylation of lysine residue 27 on histone H3 (H3K27m3) (6). Abnormal activities of DNA methyltransferases lead to epigenetic changes of many genes that contribute to carcinogenesis (7).…”

Section: Introductionmentioning

confidence: 99%

EZH2 inhibition sensitizes tamoxifen‑resistant breast cancer cells through cell cycle regulation

et al. 2017

View full text Add to dashboard Cite

Enhancer of zeste homologue 2 (EZH2), a catalytic subunit of polycomb repressive complex 2, is overexpressed in a number of different tumors including breast cancer, and serves important roles in cell cycle regulation, proliferation, apoptosis, tumorigenesis and drug resistance. However, it remains unclear whether EZH2 contributes to tamoxifen resistance in breast cancer. In the present study, the role of EZH2 in tamoxifen resistance in MCF‑7 cells was investigated. EZH2 was overexpressed in MCF‑7 tamoxifen‑resistant (MCF‑7 TamR) cells. EZH2 overexpression decreased the sensitivity of MCF‑7 cells to tamoxifen, and EZH2 knockdown improved the sensitivity of MCF‑7 TamR cells to tamoxifen. Furthermore, EZH2 knockdown induced cell cycle arrest in MCF‑7 TamR cells, accompanied by a decrease in cyclin D1 expression and an increase in p16 expression. EZH2 knockdown reduced p16 gene methylation in MCF‑7 TamR cells. These findings suggested that EZH2 overexpression may contribute to tamoxifen resistance in breast cancer, and EZH2 inhibition may reverse tamoxifen resistance in breast cancer by regulating the cell cycle via the demethylation of the p16 gene. Thus, EZH2 inhibitors may be effective for treating tamoxifen resistance in breast cancer.

show abstract

HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer

Cited by 73 publications

References 68 publications

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

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

Splice variants of cytosolic polyadenylation element–binding protein 2 (CPEB2) differentially regulate pathways linked to cancer metastasis

EZH2 inhibition sensitizes tamoxifen‑resistant breast cancer cells through cell cycle regulation

Contact Info

Product

Resources

About