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Updated: Apr 27, 2026
Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
Published on: January 12, 2020
The epigenetic factor BORIS/CTCFL regulates the NOTCH3 gene expression in cancer cells
Michele Zampieri1, Fabio Ciccarone1, Rocco Palermo2
1Department of Cellular Biotechnologies and Hematology, Faculty of Pharmacy & Medicine, Sapienza University of Rome, Rome, Italy; Pasteur Institute-Fondazione Cenci Bolognetti, Rome, Italy.
Abstract:
Aberrant upregulation of NOTCH3 gene plays a critical role in cancer pathogenesis. However, the underlying mechanisms are still unknown. We tested here the hypothesis that aberrant epigenetic modifications in the NOTCH3 promoter region might account for its upregulation in cancer cells. We compared DNA and histone methylation status of NOTCH3 promoter region in human normal blood cells and T cell acute lymphoblastic leukemia (T-ALL) cell lines, differentially expressing NOTCH3. We found that histone methylation, rather than DNA hypomethylation, contributes towards establishing an active chromatin status of NOTCH3 promoter in NOTCH3 overexpressing cancer cells. We discovered that the chromatin regulator protein BORIS/CTCFL plays an important role in regulating NOTCH3 gene expression. We observed that BORIS is present in T-ALL cell lines as well as in cell lines derived from several solid tumors overexpressing NOTCH3. Moreover, BORIS targets NOTCH3 promoter in cancer cells and it is able to induce and to maintain a permissive/active chromatin conformation. Importantly, the association between NOTCH3 overexpression and BORIS presence was confirmed in primary T-ALL samples from patients at the onset of the disease. Overall, our results provide novel insights into the determinants of NOTCH3 overexpression in cancer cells, by revealing a key role for BORIS as the main mediator of transcriptional deregulation of NOTCH3.
Insights
Histone methylation, not DNA hypomethylation, activates the NOTCH3 gene in cancer. The protein BORIS targets the NOTCH3 promoter, driving its overexpression in T-ALL and solid tumors.
Area of Science:
- Molecular Biology
- Epigenetics
- Cancer Research
Background:
- Aberrant NOTCH3 gene upregulation is implicated in cancer pathogenesis.
- The precise mechanisms driving NOTCH3 overexpression in cancer remain unclear.
- Epigenetic modifications in the NOTCH3 promoter are hypothesized to cause its upregulation.
Purpose of the Study:
- To investigate the role of epigenetic modifications in NOTCH3 promoter region in cancer cells.
- To identify the specific epigenetic changes and regulatory factors responsible for NOTCH3 overexpression.
- To explore the potential involvement of the chromatin regulator BORIS/CTCFL in NOTCH3 transcriptional deregulation.
Main Methods:
- Comparative analysis of DNA and histone methylation status in the NOTCH3 promoter region.
- Examination of NOTCH3 promoter methylation in normal blood cells versus T-ALL cell lines.
- Assessment of BORIS/CTCFL protein presence and its association with NOTCH3 promoter in various cancer cell lines and primary patient samples.
Main Results:
- Histone methylation, rather than DNA hypomethylation, was found to establish an active chromatin status at the NOTCH3 promoter in cancer cells.
- The chromatin regulator BORIS/CTCFL was identified as a key factor in NOTCH3 gene expression regulation.
- BORIS/CTCFL targets the NOTCH3 promoter in cancer cells, inducing and maintaining an active chromatin conformation, and its presence correlates with NOTCH3 overexpression in T-ALL and solid tumors.
Conclusions:
- Epigenetic deregulation, specifically histone methylation, plays a crucial role in NOTCH3 overexpression in cancer.
- BORIS/CTCFL is a critical mediator of NOTCH3 transcriptional upregulation in cancer cells.
- The findings highlight BORIS/CTCFL as a potential therapeutic target for cancers characterized by NOTCH3 overexpression.
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