Multifaceted Role of PRDM Proteins in Human Cancer

Casamassimi, Amelia; Rienzo, Monica; Zazzo, Erika Di; Sorrentino, Anna; Fiore, Donatella; Proto, Maria; Moncharmont, Bruno; Gazzerro, Patrizia; Bifulco, Maurizio; Abbondanza, Ciro

doi:10.3390/ijms21072648

Cited by 42 publications

(51 citation statements)

References 289 publications

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“…The PRDM variants show an opposite, bivalent "yin-yang" behavior with the PR-plus isoform usually acting as a tumor suppressor, and the PR-minus one functioning as an oncogene (3,7). Of note, the expression level imbalance between the two isoforms in favor of the PR-minus is often observed in many human malignancies being attributed to inactivating mutations or silencing of the complete form and/or increased expression of the PR-minus form (3,(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

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Searching for a Putative Mechanism of RIZ2 Tumor-Promoting Function in Cancer Models

et al. 2021

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Positive Regulatory Domain (PRDM) gene family members commonly express two main molecular variants, the PR-plus isoform usually acting as tumor suppressor and the PR-minus one functioning as oncogene. Accordingly, PRDM2/RIZ encodes for RIZ1 (PR-plus) and RIZ2 (PR-minus). In human cancers, genetic or epigenetic modifications induce RIZ1 silencing with an expression level imbalance in favor of RIZ2 that could be relevant for tumorigenesis. Additionally, in estrogen target cells and tissues, estradiol increases RIZ2 expression level with concurrent increase of cell proliferation and survival. Several attempts to study RIZ2 function in HeLa or MCF-7 cells by its over-expression were unsuccessful. Thus, we over-expressed RIZ2 in HEK-293 cells, which are both RIZ1 and RIZ2 positive but unresponsive to estrogens. The forced RIZ2 expression increased cell viability and growth, prompted the G2-to-M phase transition and organoids formation. Accordingly, microarray analysis revealed that RIZ2 regulates several genes involved in mitosis. Consistently, RIZ silencing in both estrogen-responsive MCF-7 and -unresponsive MDA-MB-231 cells induced a reduction of cell proliferation and an increase of apoptosis rate. Our findings add novel insights on the putative RIZ2 tumor-promoting functions, although additional attempts are warranted to depict the underlying molecular mechanism.

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Section: Introductionmentioning

confidence: 99%

“…PRDM2a/RIZ1 is also a component of the double-strand break (DSB) repair complex, which is essential for ensuring accurate repair outcome and genomic integrity maintenance (3,8). Basically, RIZ1 cooperates with the macrohistone variant mH2A1.2 to direct the choice between the antagonistic DSB repair mediators, BRCA1 and 53BP1.…”

Section: Introductionmentioning

confidence: 99%

Searching for a Putative Mechanism of RIZ2 Tumor-Promoting Function in Cancer Models

et al. 2021

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“…Recent studies have shown that E.C.M. detached cancer cells essentially need to form clusters in order to do a metabolic switch from oxidative phosphorylation to glycolysis to maintain cell proliferation and vitality 17 . Since inhibition of EZH2 was reducing the cell proliferation, we were interested in finding out whether clustering was important for high EZH2 expression in E.C.M.…”

Section: Resultsmentioning

confidence: 99%

Molecular profiling of epigenetic landscape of cancer cells during extracellular matrix detachment

Khan

Zamzami

Ahmad

et al. 2021

Sci Rep

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During cancer, a major challenge faced by oncologists is the treatment of metastasis; a leading cause of cancer-related deaths around the world. Metastasis involves a highly ordered sequence of events starting with the detachment of tumor cells from the extracellular matrix (E.C.M.). In normal cells, detachment from E.C.M. triggers programmed cell death, termed anoikis. However, tumor cells dodge their way to anoikis and spread to distant sites for initiating the metastatic program. In this work, we explored the impact of E.C.M. detachment on the expression of some major oncogenic histone methyltransferases. Results showed both EZH2 expression and its enzymatic activity were significantly increased in E.C.M. detached cancer cells when compared to the attached cells. Inhibition of EZH2 results in a significant reduction in cell proliferation, spheroids size, and induction in apoptosis in E.C.M. detached cells. Furthermore, we observed a reduction in EZH2 expression levels in single cells when compared to clusters of E.C.M. detached cells. Finally, we combined the EZH2 inhibition with AMPK, known to be highly expressed in E.C.M. detached cancer cells and observed antagonistic effects between the two pathways. The observed results clearly showed that E.C.M. detached cancer cells require oncogenic EZH2 and can be targeted by EZH2 inhibitors.

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“…Our study indicates the potential role of MT1M in biological processes. PRDM1 has been associated with cancer progression, metastasis, and altered expression correlated with poor prognosis in lung cancer [ 37 ]. In ovarian CSCs, PRDM1 might be used as prognostic tool and serve as a new therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis and verification of molecular targets in ovarian cancer stem-like cells

Behera

Ashraf

Srivastava

et al. 2020

Heliyon

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Background Epithelial ovarian cancer (EOC) is a lethal and aggressive gynecological malignancy. Despite recent advances, existing therapies are challenged by a high relapse rate, eventually resulting in disease recurrence and chemoresistance. Emerging evidence indicates that a subpopulation of cells known as cancer stem-like cells (CSLCs) exists with non-tumorigenic cancer cells (non-CSCs) within a bulk tumor and is thought to be responsible for tumor recurrence and drug-resistance. Therefore, identifying the molecular drivers for cancer stem cells (CSCs) is critical for the development of novel therapeutic strategies for the treatment of EOC. Methods Two gene datasets were downloaded from the Gene Expression Omnibus (GEO) database based on our search criteria. Differentially expressed genes (DEGs) in both datasets were obtained by the GEO2R web tool. Based on log 2 (fold change) >2, the top thirteen up-regulated genes and log 2 (fold change) < -1.5 top thirteen down-regulated genes were selected, and the association between their expressions and overall survival was analyzed by OncoLnc web tool. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathways analysis, and protein-protein interaction (PPI) networks were performed for all the common DEGs found in both datasets. SK-OV-3 cells were cultured in an adherent culture medium and spheroids were generated in suspension culture with CSCs specific medium. RNA from both cell population was extracted to validate the selected DEGs expression by q-PCR. Growth inhibition assay was performed in SK-OV-3 cells after carboplatin treatment. Results A total of 200 DEGs, 117 up-regulated and 83 down-regulated genes were commonly identified in both datasets. Analysis of pathways and enrichment tests indicated that the extracellular matrix part, cell proliferation, tissue development, and molecular function regulation were enriched in CSCs. Biological pathways such as interferon-alpha/beta signaling, molecules associated with elastic fibers, and synthesis of bile acids and bile salts were significantly enriched in CSCs. Among the top 13 up-regulated and down-regulated genes, MMP1 and PPFIBP1 expression were associated with overall survival. Higher expression of ADM, CXCR4, LGR5, and PTGS2 in carboplatin treated SK-OV-3 cells indicate a potential role in drug resistance. Conclusions The molecular signature and signaling pathways enriched in ovarian CSCs were identified by bioinformatics analysis. This analysis could provide further research ideas to find the new mechanism and novel potential therapeutic targets for ovarian CSCs.

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Multifaceted Role of PRDM Proteins in Human Cancer

Cited by 42 publications

References 289 publications

Searching for a Putative Mechanism of RIZ2 Tumor-Promoting Function in Cancer Models

Searching for a Putative Mechanism of RIZ2 Tumor-Promoting Function in Cancer Models

Molecular profiling of epigenetic landscape of cancer cells during extracellular matrix detachment

Bioinformatics analysis and verification of molecular targets in ovarian cancer stem-like cells

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