Abstract
BackgroundMNAT1 (menage a trois 1, MAT1), a cyclin-dependent kinase-activating kinase (CAK) complex, high expresses in various cancers and is involved in cancer pathogenesis. However, mechanisms underlying its regulation in carcinogenesis are unclear.MethodsThe tissue microarray of colorectal cancer (CRC) was used to evaluate MNAT1 expressions in CRC tissues using immunohistochemistry, CRC cell lines were also detected MNAT1 expression using Western-blotting. MNAT1 and shMNAT1 vectors were constructed, and transfected into CRC cells. Cell growths of the transfected cells were observed using MTT and colony formation. The affects of MNAT1 on p53 expression were analyzed using Western-blotting and Real-time PCR. Immunoprecipitation assay was used to analyze the interaction p53 and MNAT1, and Western-blotting was used to test the effects of MNAT1 on p53 downstream molecules. The apoptosis of CRC cells with MNAT1 or shMNAT1 were analyzed using flow cytometry. BABL/c athymic nude mice were used to observe the effect of MNAT1 on CRC cell growth in vivo.ResultsMNAT1 was found to be overexpressed in CRC tissues and cells, and MNAT1 expressions in CRC tissue samples were associated with CRC carcinogenesis and poor patient outcomes. MNAT1-knockin increased CRC cell growth and colony formation, and MNAT1-knockdown dramatically decreased cell motility and invasion. MNAT1 physically interacted with p53, MNAT1 also increased the interaction of MDM2 with p53. Strikingly, MNAT1 mediated p53 ubiquitin-degradation. MNAT1 shortened p53 half-life, and ectopic MNAT1 expression decreased p53 protein stability. Moreover, MNAT1 induced RAD51 and reduced p21, cleaved-caspase3, cleaved-PARP and BAX expression. MNAT1 inhibited CRC cell apoptosis. shMANT1 decreased tumor growths in nude mice following p53 increase.ConclusionMNAT1 binds to p53, mediates p53 ubiquitin-degradation through MDM2, increases cell growth and decreases cell apoptosis, and finally promotes CRC malignance. MNAT1 binding to p53 and mediating p53 ubiquitin-degradation axis represents a novel molecular joint in the p53 pathway.
Highlights
Menage a trois 1 (MNAT1), a cyclin-dependent kinase-activating kinase (CAK) complex, high expresses in various cancers and is involved in cancer pathogenesis
We found that MNAT1 is highly expressed in Colorectal cancer (CRC) tissues, its expression was associated with CRC carcinogenesis and poor patient outcomes
The immunohistochemical results showed that MNAT1 was significantly high in CRC tissues when compared with the matched adjacent normal tissues (Fig. 1b, c. p = 0.042)
Summary
MNAT1 (menage a trois 1, MAT1), a cyclin-dependent kinase-activating kinase (CAK) complex, high expresses in various cancers and is involved in cancer pathogenesis. Overexpression of specific oncogenes or low expression of tumor suppressor genes in the epithelium results in the formation of a hyperproliferative mucosa, produces a benign adenoma, and eventually forms a carcinoma [2,3,4]. This process is orchestrated by different proteins, such as, Wnt, bone morphogenetic protein (BMP) and transforming growth factor (TGF)-β, along with p53 [5]. Alterations molecule pathways, such as cell cycle, cell proliferation, and apoptosis are involved in CRC onset. These alterations are responsible for colorectal epithelium carcinogenesis, which evenly confer individual susceptibility to cancers when they are germlines [6,7,8]
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