The epigenetic factor CTCF-L/BORIS regulates the NOTCH3 gene transcription in cancer cells

Aberrant up-regulation 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 up-regulation in cancer cells. We compared DNA and histone methylation status of NOTCH3 promoter region in human normal blood cells and cancer cell lines from acute T lymphoblastic leukaemia (T-ALL) discordant for NOTCH3 expression. 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/CTCF-L plays an important role in NOTCH3 expression. We observed that BORIS is present in T-ALL cell lines as well as in cell lines of various cancer origin 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 by revealing a role for BORIS as mediator of transcriptional deregulation of NOTCH3 in cancer cells.