BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype

Gorodetska, Ielizaveta; Lukiyanchuk, Vasyl; Peitzsch, Claudia; Kozeretska, Iryna; Dubrovska, Anna

doi:10.1002/ijc.32323

Cited by 58 publications

(57 citation statements)

References 52 publications

(95 reference statements)

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“…EZH2 is aberrantly expressed in glioma and has strong effects on PCa proliferation and metastasis [28][29][30]. Studies show that EZH2 functions in the maintenance of cancer stem-like cell (CSC) properties [31]. CSCs take part in tumor proliferation, recurrence, invasion, and chemoradioresistance, which makes a new concept of tumorigenicity and progression [32].…”

Section: Discussionmentioning

confidence: 99%

Downregulation of circ-TRPS1 suppressed prostatic cancer prognoses by regulating miR-124-3p/EZH2 axis-mediated stemness

Sha

Lei

Han

et al. 2020

Preprint

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Background: Abnormal circular RNA (circRNA) expression correlates with human traits such as many kinds of cancers. Though circRNAs have links to cancer, they have less characterization in metastatic castration-resistant prostate cancer (PCa), which is main reason for PCa mortality.Methods: Therefore, high-throughput sequencing was used for selected circRNA profiles. We performed RT-qPCR to determine circ-TRPS1 expression regarding PCa tissues. We used fluorescence in situ hybridization (FISH) to detect circ-TRPS1 expression and circ-TRPS1 subcellular localization in PCa tissues. circ-TRPS1 expression in PCa cells was selectively regulated. We employed CCK8, transwell assays to monitor the cell proliferation and invasion, respectively. We employed dual-luciferase reporter and RNA pulldown assays to verify the relationship among circ-TRPS1, miR-124-3p, and EZH2. We examined the circ-TRPS1 effects on PCa cell metastasis and proliferation in vivo through a subcutaneous xenograft model as well as an intravenous tail injection model of nude mice.Results: The result showed that circ-TRPS1 was upregulated significantly in high-grade PCa tissues or cell lines. High circ-TRPS1 expression correlated to aggressive PCa phenotypes. Knockdown of circ-TRPS1 suppressed PCa proliferation and metastasis through targeting miR-124-3p/EZH2 axis-mediated stemness in PCa, which was validated by luciferase reporter assays. EZH2 overexpression or miR-124-3p inhibition reversed the inhibition of circ-TRPS1 silencing in PCa cell migration and proliferation by recovering stemness.Conclusion: In summary, data demonstrated that circ-TRPS1 suppressed PCa progression through functioning similar to a miR-124-3p sponge to enhance EZH2 expression and cancer stem-like cell differentiation. Thus, circ-TRPS1 might be a candidate target for PCa treatment.

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Section: Discussionmentioning

confidence: 99%

Downregulation of circ-TRPS1 suppressed prostatic cancer prognoses by regulating miR-124-3p/EZH2 axis-mediated stemness

Sha

Lei

Han

et al. 2020

Preprint

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“…EZH2 not only promotes the formation of cancer stem cells, but also expand the aggressive cancer cells population and lead to cancer progression [57]. Furthermore, EZH2 can also co-regulate prostate cancer stem cell properties with BRCA1 [58].…”

Section: Discussionmentioning

confidence: 99%

“…In the genes of MEmagenta module ( Supplementary Table S1), we found that the known genes closely related to cancer stemness in non-prostate cancer, such as BRCA1 [31], EZH2 [31], FOXM1 [32], CDC20 [33] and CDCA8 [34], were all clustered in this module, indicating these genes were also closely related to the stemness of prostate cancer cells. From supplementary table S1, we also found that EZH2 was the most signi cant gene in the correlation with stemness of PCa cells.…”

Section: Correlation Analysis Between Cancer Cell Stemness and Clinicmentioning

confidence: 92%

Copy Number Variation and Transcription Regulation of Genes and Immune Microenvironment of Tumor Affect the Stemness of Prostate Cancer Cell

Dai¹,

Liu²

2020

Preprint

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Background: Prostate cancer stem cells (pCSC) play an important role in tumor metastasis through multiple pathways. From gene, protein to microenvironment, there are many factors affecting the cell stemness of prostate cancer (PCa). However, the effective factors affecting the stemness of prostate cancer cells are still unclear.Methods: Based on the transcription data of prostate cancer in the TCGA database, WGCNA (Weighted Gene Co-expression Network Analysis) and stemness scores were used to find important stemness gene module. According to ATAC-seq and genomic data, analyze their relationship with stemness. The interaction of stemness genes was analyzed with STRING (functional protein association networks) database. Furthermore, based on the immune microenvironment score, the relationship between immune and stemness was analyzed.Results: The most important stemness gene module in prostate cancer was obtained with WGCNA method; then a positive correlation between the gene CNVs (Copy Number Variants) of the most important stemness gene module and PCa stemness was found, as well as a positive correlation between the gene CNVs and Gleason score of PCa was also drug out. Further, the key transcriptional regulators of the most important stemness genes in PCa were obtained. In addition, it's found that immune cells, especially CD8+T cells and M1 macrophages, suppressed the stemness of PCa cells. Finally, by analyzing the protein interactions and the relationship between genes and immune cells, we found that interaction of the proteins of the most important stemness genes module and the relationship between these genes and immune cells of microenvironment of PCa were all important in affecting the stemness of PCa cells.Conclusions: By analyzing multi-omics data of clinical specimen, we got the most important stemness genes and their important transcriptional regulators in PCa; and further mining analysis showed that the stemness of PCa cells is positive regulated by the CNVs and the interaction of the proteins of the most important stemness genes, and negatively regulated by the immune cells of the microenvironment of prostate cancer.

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“…Yi and colleagues observed abnormal DNA methylation of CD133, a CSC marker, in colorectal and glioblastoma tumors [ 236 ]. Gorodetska and colleagues observed that EZH2/BRCA1 signaling mechanisms play an important role in the maintenance of prostate CSCs properties [ 238 ]. EMT aid in the generation of cells with stem cell characteristics and is modulated by epigenetic mechanisms [ 239 , 240 ].…”

Section: Properties Of Cancer Stem Cellsmentioning

confidence: 99%

Advances in Therapeutic Targeting of Cancer Stem Cells within the Tumor Microenvironment: An Updated Review

Dzobo

Senthebane

Ganz

et al. 2020

Cells

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Despite great strides being achieved in improving cancer patients’ outcomes through better therapies and combinatorial treatment, several hurdles still remain due to therapy resistance, cancer recurrence and metastasis. Drug resistance culminating in relapse continues to be associated with fatal disease. The cancer stem cell theory posits that tumors are driven by specialized cancer cells called cancer stem cells (CSCs). CSCs are a subpopulation of cancer cells known to be resistant to therapy and cause metastasis. Whilst the debate on whether CSCs are the origins of the primary tumor rages on, CSCs have been further characterized in many cancers with data illustrating that CSCs display great abilities to self-renew, resist therapies due to enhanced epithelial to mesenchymal (EMT) properties, enhanced expression of ATP-binding cassette (ABC) membrane transporters, activation of several survival signaling pathways and increased immune evasion as well as DNA repair mechanisms. CSCs also display great heterogeneity with the consequential lack of specific CSC markers presenting a great challenge to their targeting. In this updated review we revisit CSCs within the tumor microenvironment (TME) and present novel treatment strategies targeting CSCs. These promising strategies include targeting CSCs-specific properties using small molecule inhibitors, immunotherapy, microRNA mediated inhibitors, epigenetic methods as well as targeting CSC niche-microenvironmental factors and differentiation. Lastly, we present recent clinical trials undertaken to try to turn the tide against cancer by targeting CSC-associated drug resistance and metastasis.

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BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype

Cited by 58 publications

References 52 publications

Downregulation of circ-TRPS1 suppressed prostatic cancer prognoses by regulating miR-124-3p/EZH2 axis-mediated stemness

Downregulation of circ-TRPS1 suppressed prostatic cancer prognoses by regulating miR-124-3p/EZH2 axis-mediated stemness

Copy Number Variation and Transcription Regulation of Genes and Immune Microenvironment of Tumor Affect the Stemness of Prostate Cancer Cell

Advances in Therapeutic Targeting of Cancer Stem Cells within the Tumor Microenvironment: An Updated Review

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