Abstract
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.
Highlights
Disruptor of telomeric silencing-1-like (DOT1L) has emerged as an anticancer target for mixed lineage leukemia (MLL)-associated leukaemias; its functional role in solid tumours is largely unknown
Because Snail, ZEB1 and ZEB2 modulate cancer stem cell (CSC) activity[11,21], we further explored whether DOT1L-induced CSC-like properties is mediated by these epithelial–mesenchymal transition (EMT)-TFs
In this study, we demonstrated that cooperation of DOT1L with c-Myc-p300 is important for regulation of both the EMT and CSC in breast cancer by epigenetic activation of EMT-transcription factors (EMT-TFs), providing a novel mechanism of epigenetic regulation of DOT1L-mediated transcription of EMT enhancers (Fig. 5e)
Summary
DOT1L has emerged as an anticancer target for MLL-associated leukaemias; its functional role in solid tumours is largely unknown. 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. We find that DOT1L forms a novel transcriptional active complex with c-Myc and p300 to enhance epigenetic derepression of EMT-TFs and promote EMT-induced CSC properties in human breast cancer. Our findings demonstrate functional role of potential oncogene DOT1L in promoting multistep breast carcinogenesis associated with EMT and stem cell-like phenotype as a novel epigenetic regulator of EMT-TFs, suggesting DOT1L to be a promising target for aggressive breast cancer therapy
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