Abstract
MUC1 is a transmembrane mucin that can promote cancer progression, and its upregulation correlates with a worse prognosis in colon cancer. We examined the effects of overexpression of MUC1 in colon cancer cells, finding that it induced epithelial to mesenchymal transition (EMT), including enhanced migration and invasion, and increased Akt phosphorylation. When the clones were treated with the aspirin metabolite salicylate, Akt phosphorylation was decreased and EMT inhibited. As the salicylate motif is necessary for the activity of the lysine acetyltransferase (KAT) inhibitor anacardic acid, we hypothesized these effects were associated with the inhibition of KAT activity. This was supported by anacardic acid treatment producing the same effect on EMT. In vitro KAT assays confirmed that salicylate directly inhibited PCAF/Kat2b, Tip60/Kat5 and hMOF/Kat8, and this inhibition was likely involved in the reversal of EMT in the metastatic prostate cancer cell line PC-3. Salicylate treatment also inhibited EMT induced by cytokines, illustrating the general effect it had on this process. The inhibition of both EMT and KATs by salicylate presents a little explored activity that could explain some of the anti-cancer effects of aspirin.
Highlights
MUC1 is a transmembrane mucin providing protective functions in epithelial cells against stressors including bacterial infection[1] and chemical agents[2]
To investigate the effects of overexpressing MUC1, the colon cancer cell line HT29 was transfected with a plasmid containing full length MUC1 with 23 tandem repeats, or empty vector control
The phenotype suggested Epithelial to mesenchymal transition (EMT) induction, and real time PCR demonstrated a decrease in mRNA levels of the epithelial marker e-cadherin, and an increase in the mesenchymal marker vimentin (Fig. 1a)
Summary
MUC1 is a transmembrane mucin providing protective functions in epithelial cells against stressors including bacterial infection[1] and chemical agents[2]. MUC1 levels vary in the gastrointestinal tract, being highly expressed in the stomach, but not in the colon, expression increases during conditions of chronic inflammation such as ulcerative colitis[4]. Expression of human MUC1 in a mouse inflammation model was shown to increase the rate of progression to colon cancer[8]. Whitney U-test was performed to evaluate if these means differed between the MUC1 expressing clones and the control clones. The migration rate of the MUC1 expressing clones relative to the vector control clones were analysed using an in vitro “wound healing” assay. (c) The invasive ability of the MUC1 clones and vector control clones were evaluated using an in vitro gel-membrane scaffold simulating the extracellular matrix. Clones overexpressing MUC1 were transfected with siRNA that knocked down MUC11 (muc1) and non-specific control siRNA (scr)
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