In:
The FEBS Journal, Wiley, Vol. 290, No. 2 ( 2023-01), p. 502-520
Abstract:
DOT1L, a specific H3K79 methyltransferase, has a tumour‐promoting role in various cancers, including triple‐negative breast cancer (TNBC). However, the molecular mechanism by which the deregulated DOT1L promotes cancer progression is unclear. Herein, we show that a significantly higher basal level of DOTL1 strongly correlates with MTDH, an oncogene, in clinical TNBC patient cohorts and mediates TNBC progression by enhancing MTDH‐induced angiogenesis. In parallel, severe combined immunodeficiency mice‐bearing MDA‐MB‐231 cells with MTDH‐Wt or MTDHΔ7 (spliced isoform of MTDH) overexpression constructs showed enhanced blood vessel formations at the tumour site in comparison with control groups. Selective inhibition of DOT1L by EPZ004777, a specific DOT1L inhibitor, or siDOT1L, significantly impaired MTDH‐induced proliferation, invasion and angiogenic markers expression in TNBC cells. ChIP assay revealed that Dot1L promotes MTDH‐Wt/Δ7 transcription by increasing H3K79me3 levels on its promoter. Dot1L depletion reversed this effect. Mechanistically, DOT1L‐induced MTDH caused enhanced nuclear factor kappa B (NF‐κB) occupancy on the hypoxia‐inducible factor1α (HIF1α) promoter and increased its transcription, leading to elevated levels of proangiogenic mediators in TNBC cells. Moreover, the condition media obtained from MDA‐MB‐231 cells stably expressing either MTDH‐Wt or MTDHΔ7 treated with EPZ004777 or Bay‐11‐7082 (NF‐κB inhibitor) or FM19G11 (HIF1α inhibitor) significantly inhibited MTDH‐induced tube formation in human umbilical vein endothelial cells, rat aortic ring sprouting and vessel formations by chick chorioallantoic membrane assay mimicking physiological angiogenic vasculature. Collectively, our findings reveal a novel epigenetic regulation of MTDH by DOTL1, which drives angiogenesis, and that the therapeutic disruption of the DOT1L‐MTDH‐NF‐κB‐HIF1α axis may have usefulness in the management of TNBC.
Type of Medium:
Online Resource
ISSN:
1742-464X
,
1742-4658
Language:
English
Publisher:
Wiley
Publication Date:
2023
detail.hit.zdb_id:
2172518-4
SSG:
12
