The ALKBH family of
proteins are highly expressed in various types of human
cancer where they are involved in
tumor growth and progression. However, multiple
isoforms of ALKBH exist and the effect of individual
isoforms on the development of
urinary bladder cancer is unknown, particularly the molecular mechanisms involved in the progression from a noninvasive to invasive phenotype. We examined the role and function of ALKBH2 in human
bladder cancer development in vitro and provide the first report that suppression of ALKBH2 in a human urothelial
carcinoma cell line, KU7, reduces the expression of the transmembrane
mucin protein, MUC1, and induces G1 cell cycle arrest. Moreover, reduction of ALKBH2 suppressed epithelial to mesenchymal transition (EMT) via increasing
E-cadherin and decreasing
vimentin expression. Transfection of MUC1
siRNA inhibited cell proliferation and EMT to the same extent as ALKBH2 gene silencing in vitro. ALKBH2 knockdown significantly suppressed MUC1 expression and
tumor volume of
bladder cancers in vivo as assessed in an orthotopic mouse model using ALKBH2
shRNA transfected KU7 cells. Immunohistochemical examination showed high expression levels of ALKBH2 in human urothelial
carcinoma samples, especially in high-grade, superficially and deeply invasive
carcinomas (pT(1) and >pT(2)), and in
carcinoma in situ but not in normal urothelium. This study demonstrates that ALKBH2 is an upstream molecule of the
oncoprotein, MUC1, and regulates cell cycle and EMT, resulting in progression of urothelial
carcinomas.