Clinical Correlations of Polycomb Repressive Complex 2 in Different Tumor Types

Erokhin, Maksim; Четверина, О. А.; Győrffy, Balázs; Tatarskiy, Victor V.; Mogila, Vladic; Shtil, Alexander А.; Roninson, Igor B.; Moreaux, Jérôme; Georgiev, Pavel; Cavalli, Giacomo; Chetverina, Darya

doi:10.3390/cancers13133155

Cited by 17 publications

(9 citation statements)

References 126 publications

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“… 118 With the aim to identify the cancer types in which treatment using PRC2 inhibitors could be beneficial, a genomic and transcriptomic analysis using available databases on clinical tumor samples and a panel of tumor cell lines has been performed, revealing a correlation of EZH2, SUZ12 or EED amplifications with poor prognosis in a subclass of human cancers like renal papillary cell carcinoma, low-grade glioma and hepatocellular carcinoma. 119 Interestingly, GOFs of PRC2 subunits are also anti-correlated with poor prognosis in some cancers like gastric cancer and thymoma, suggesting a tumor suppressor function of PRC2 in those cases.…”

Section: Polycomb In Cancermentioning

confidence: 99%

Mechanisms of Polycomb group protein function in cancer

2022

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Cancer arises from a multitude of disorders resulting in loss of differentiation and a stem cell-like phenotype characterized by uncontrolled growth. Polycomb Group (PcG) proteins are members of multiprotein complexes that are highly conserved throughout evolution. Historically, they have been described as essential for maintaining epigenetic cellular memory by locking homeotic genes in a transcriptionally repressed state. What was initially thought to be a function restricted to a few target genes, subsequently turned out to be of much broader relevance, since the main role of PcG complexes is to ensure a dynamically choregraphed spatio-temporal regulation of their numerous target genes during development. Their ability to modify chromatin landscapes and refine the expression of master genes controlling major switches in cellular decisions under physiological conditions is often misregulated in tumors. Surprisingly, their functional implication in the initiation and progression of cancer may be either dependent on Polycomb complexes, or specific for a subunit that acts independently of other PcG members. In this review, we describe how misregulated Polycomb proteins play a pleiotropic role in cancer by altering a broad spectrum of biological processes such as the proliferation-differentiation balance, metabolism and the immune response, all of which are crucial in tumor progression. We also illustrate how interfering with PcG functions can provide a powerful strategy to counter tumor progression.

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Section: Polycomb In Cancermentioning

confidence: 99%

Mechanisms of Polycomb group protein function in cancer

2022

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“…PRC2 comprised three core components (EZH2, SUZ12, and EED). EZH2 has hmtase activity, which is maintained by the presence of SUZ12 and EED ( Erokhin et al, 2021 ). We used TCGA databases to analyze the expression levels of PRC2 components in ESCA.…”

Section: Resultsmentioning

confidence: 99%

Identification and Validation of Chromobox Family Members as Potential Prognostic Biomarkers and Therapeutic Targets for Human Esophageal Cancer

et al. 2022

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Background: Chromobox family proteins (CBXs) are vital components of epigenetic regulation complexes and transcriptionally inhibit target genes by modifying the chromatin. Accumulating evidence indicates that CBXs are involved in the initiation and progression of multiple malignancies. However, the expression, function, and clinical relevance such as the prognostic and diagnostic values of different CBXs in esophageal carcinoma (ESCA) are still unclear.Methods: We applied Oncomine, TCGA, GEO, GEPIA, UALCAN, Kaplan–Meier plotter, cBioPortal, Metascape, and TIMER to investigate the roles of CBX family members in ESCA. Additionally, quantitative real-time PCR (RT-PCR), western blot, and immunofluorescence were used to verify the expression of CBX family members in ESCA clinical samples.Results: Compared with normal tissues, the mRNA expression levels of CBX1/3/8 were significantly increased in ESCA, whereas CBX7 mRNA expression was reduced in both the TCGA cohort and GEO cohort. In the TCGA cohort, ROC curves suggested that CBX1/2/3/4/8 had great diagnostic value in ESCA, and the AUCs were above 0.9. Furthermore, upregulation of CBX1/3/8 and downregulation of CBX7 were closely related to the clinicopathological parameters in ESCA patients, such as tumor grades, tumor nodal metastasis status, and TP53 mutation status. The survival analysis indicated that higher CBX1/3/8 mRNA expressions and lower CBX7 expression suggested an unfavorable prognosis in ESCA. High genetic change rate (52%) of CBXs was found in ESCA patients. Functions and pathways of mutations in CBXs and their 50 frequently altered neighbor genes in ESCA patients were investigated; the results showed that DNA repair and DNA replication were correlated to CBX alterations. Moreover, we found a significant correlation between the expression level of CBX family members and the infiltration of immune cells in ESCA. Finally, we verified the expression of CBX family members in clinical samples and found the results were consistent with the databases.Conclusion: Our study implied that CBX1/3/7/8 are potential targets of precision therapy for ESCA patients and new biomarkers for the prognosis.

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“…Apart from the DDX3X: MLLT10 gene fusion, OGM could also unravel deletions in ARPP21, NF1, and SUZ12. SUZ12 is part of the polycomb repressive complex 2 (PRC2) that in turn is responsible for the methylation of H3K27 (36,37). This methylation enables DOT1L with its complex to bind and exert its function as a transcription initiator for H3K79 (34).…”

Section: Discussionmentioning

confidence: 99%

Broad genomic workup including optical genome mapping uncovers a DDX3X: MLLT10 gene fusion in acute myeloid leukemia

et al. 2022

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In acute myeloid leukemia (AML), treatment decisions are currently made according to the risk classification of the European LeukemiaNet (ELN), which is based on genetic alterations. Recently, optical genome mapping (OGM) as a novel method proved to yield a genome-wide and detailed cytogenetic characterization at the time of diagnosis. A young female patient suffered from a rather unexpected aggressive disease course under FLT3 targeted therapy in combination with induction chemotherapy. By applying a “next-generation diagnostic workup“ strategy with OGM and whole-exome sequencing (WES), a DDX3X: MLLT10 gene fusion could be detected, otherwise missed by routine diagnostics. Furthermore, several aspects of lineage ambiguity not shown by standard diagnostics were unraveled such as deletions of SUZ12 and ARPP21, as well as T-cell receptor recombination. In summary, the detection of this particular gene fusion DDX3X: MLLT10 in a female AML patient and the findings of lineage ambiguity are potential explanations for the aggressive course of disease. Our study demonstrates that OGM can yield novel clinically significant results, including additional information helpful in disease monitoring and disease biology.

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Clinical Correlations of Polycomb Repressive Complex 2 in Different Tumor Types

Cited by 17 publications

References 126 publications

Mechanisms of Polycomb group protein function in cancer

Mechanisms of Polycomb group protein function in cancer

Identification and Validation of Chromobox Family Members as Potential Prognostic Biomarkers and Therapeutic Targets for Human Esophageal Cancer

Broad genomic workup including optical genome mapping uncovers a DDX3X: MLLT10 gene fusion in acute myeloid leukemia

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