DOT1L cooperates with the c-Myc-p300 complex to epigenetically derepress CDH1 transcription factors in breast cancer progression

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.

Phenotypic, transcriptomic, and genomic features of clonal plasma cells in light-chain amyloidosis

“…Even though multidimensional scaling analysis showed differences between both groups of PCs ( Figure 1B), there were only 38 genes significantly deregulated (3 upregulated and 35 downregulated) in AL PCs (excluding 22 immunoglobulin coding genes, which are physiologically upregulated in normal PCs and mainly reflect differences between clonal vs polyclonal PCs; supplemental Excel File 1). Interestingly, the CDH1 and RCAN tumor-suppressor genes and the GLIPR1 and FAS proapoptotic genes [14][15][16][17][18] were all significantly downregulated in AL; in contrast, IFITM1, which has been associated with more aggressive solid tumors, 19 was overexpressed in clonal PCs. It is worth noting that CD19 and CD81 mRNAs were significantly decreased in AL, confirming the correlation between the iPEP and the GEP of clonal vs normal PCs.…”

Prognostic and therapeutic value of disruptor of telomeric silencing-1-like (DOT1L) expression in patients with ovarian cancer

“…Consequently, DOT1L is a drug target for MLL-rearranged leukemia [11, 12]. Furthermore, a few recent publications have reported that DOT1L plays crucial roles not only in leukemia, but also in solid tumors, such as breast cancer, esophageal squamous cell carcinoma, colorectal cancer, prostate cancer, and gastric cancer [13–19]. Moreover, DOT1L inhibitors have shown effective suppression of proliferation, migration, and invasion of breast cancer [20].…”

Direct interaction between miR-203 and ZEB2 suppresses epithelial–mesenchymal transition signaling and reduces lung adenocarcinoma chemoresistance

“…EMT is a process whereby cells acquire morphologic and molecular alterations facilitating tumor metastasis and progression [23,[24][25][26]. In previous studies, EMT signaling has been suggested to play a critical role in resistance to DDP [27,28].…”