DOT1L has emerged as an anticancer target for MLL-associated leukaemias; however, its functional role in solid tumours is largely unknown. Here we identify that DOT1L cooperates with c-Myc and p300 acetyltransferase to epigenetically activate epithelial–mesenchymal transition (EMT) regulators in breast cancer progression. DOT1L recognizes SNAIL, ZEB1 and ZEB2 promoters via interacting with the c-Myc-p300 complex and facilitates lysine-79 methylation and acetylation towards histone H3, leading to the dissociation of HDAC1 and DNMT1 in the regions. The upregulation of these EMT regulators by the DOT1L-c-Myc-p300 complex enhances EMT-induced breast cancer stem cell (CSC)-like properties. Furthermore, in vivo orthotopic xenograft models show that DOT1L is required for malignant transformation of breast epithelial cells and breast tumour initiation and metastasis. Clinically, DOT1L expression is associated with poorer survival and aggressiveness of breast cancers. Collectively, we suggest that cooperative effect of DOT1L and c-Myc-p300 is critical for acquisition of aggressive phenotype of breast cancer by promoting EMT/CSC.

Immune system activation contributes to the pathogenesis of hypertension and the resulting progression of chronic kidney disease (CKD). In this regard, we recently identified a role for pro-inflammatory Th1 T lymphocyte responses in hypertensive kidney injury. As Th1 cells generate IFN-γ and TNF-α, we hypothesized that IFN-γ and TNF-α propagate renal damage during hypertension induced by activation of the renin-angiotensin system (RAS). Therefore, after confirming that mice genetically deficient of Th1 immunity were protected from kidney glomerular injury despite a preserved hypertensive response, we subjected mice lacking IFN-γ or TNF-α to our model of hypertensive CKD. IFN-deficiency had no impact on blood pressure elevation or urinary albumin excretion during chronic angiotensin II infusion. By contrast, TNF-deficient (KO) mice had blunted hypertensive responses and reduced end-organ damage in our model. As Ang II-infused TNF KO mice had exaggerated eNOS expression in the kidney and enhanced nitric oxide (NO) bioavailability, we examined the actions of TNF-α generated from renal parenchymal cells in hypertension by transplanting wild-type or TNF KO kidneys into wild-type recipients prior to the induction of hypertension. Transplant recipients lacking TNF solely in the kidney had blunted hypertensive responses to Ang II and augmented renal eNOS expression, confirming a role for kidney-derived TNF-α to promote Ang II-induced blood pressure elevation by limiting renal NO generation.