Overexpression of maelstrom promotes bladder urothelial carcinoma cell aggressiveness by epigenetically downregulating MTSS1 through DNMT3B

Abstract

We have recently identified and characterized a novel oncogene, maelstrom (MAEL) from 1q24, in the pathogenesis of hepatocellular carcinoma. In this study, MAEL was investigated for its oncogenic role in urothelial carcinoma of the bladder (UCB) tumorigenesis/aggressiveness and underlying molecular mechanisms. Here, we report that overexpression of MAEL in UCB is important in the acquisition of an aggressive and/or poor prognostic phenotype. In UCB cell lines, knockdown of MAEL by short hairpin RNA is sufficient to inhibit cell growth, invasiveness/metastasis and suppressed epithelial-mesenchymal transition (EMT), whereas ectopic overexpression of MAEL promoted cell growth, invasive and/or metastatic capacity and enhanced EMT both in vitro and in vivo. We further demonstrate that MAEL could induce UCB cell EMT by downregulating a critical downstream target, the metastasis suppressor 1 (MTSS1) gene, ultimately leading to an increased invasiveness of cancer cells. Notably, overexpression of MAEL in UCB cells substantially enhanced the enrichment of DNA methyltrans-ferase (DNMT)3B and histone deacetylase (HDAC)1/2 on the promoter of the MTSS1, and thereby epigenetically suppressing the MTSS1 transcription. Downregulation of MTSS1 by MAEL in UCB cells is partially dependent on DNMT3B. Furthermore, we identify that beside the gene amplification of MAEL, miR-186 is a key negative regulator of MAEL and downregulation of miR-186 is another important mechanism for MAEL overexpression in UCBs. These data suggest that overexpression of MAEL, caused by gene amplification and/or decreased miR-186, has a critical oncogenic role in UCB pathogenesis by downregulation of MTSS1, and MAEL could be used as a novel prognostic marker and/or effective therapeutic target for human UCB.

Kaempferol Modulates DNA Methylation and Downregulates DNMT3B in Bladder Cancer

“…We found that Kae inhibited the expression of DNMT3B without altering the expression of DNMT1 or DNMT3A, in both T24 and 5637 cells in vitro and in the xenografts. In bladder cancer, the increasing of DNMT3B silences some tumor suppressors and thereby promote tumor progression [37]. Targeting DNMT3B may inhibit the tumor progression and increase the sensitivity to chemotherapy [38].…”

Maelstrom Directs Myeloid-Derived Suppressor Cells to Promote Esophageal Squamous Cell Carcinoma Progression via Activation of the Akt1/RelA/IL8 Signaling Pathway

“…1), urothelial carcinoma of the bladder (UCB; ref. 7), and colorectal cancer (8). A growing body of evidence has shed considerable light on the important roles of MAEL in cancer progression (9,10).…”

“…A previous study demonstrates that MAEL is an important player in the progression of HCC by activating Akt/GSK3b/Snail signaling (1). MAEL, regulated by miR-186, can promote tumor aggressiveness by epigenetically downregulating the metastasis suppressor 1 (MTSS1) gene through DNA methyltransferase (DNMT)3B in UCB (7). In colorectal cancer, MAEL can induce epithelial-mesenchymal transition (EMT) and stem cell properties to promote the progression of patients with colorectal cancer (8).…”

CSTF2-Induced Shortening of the RAC1 3′UTR Promotes the Pathogenesis of Urothelial Carcinoma of the Bladder

“…IHC studies were performed following a standard streptavidinbiotin-peroxidase complex method (13). Slides were incubated respectively with primary antibodies against RAC1 (Proteintech), CSTF2, FIP1, CPSF6 (Abcam; 1:200 dilution), PABPN1, CFIM25 (Abcam), and CFIM68 (Santa Cruz Biotechnology; 1:500 dilution).…”