The molecular mechanisms by which arsenic (As ( 3+) ) causes human cancers 
remain to be fully elucidated. Enhancer of zeste homolog 2 (EZH2) is the 
catalytic subunit of polycomb-repressive complexes 2 (PRC2) that promotes 
trimethylation of lysine 27 of histone H3, leading to altered expression of 
tumor suppressors or oncogenes. In the present study, we determined the effect 
of As ( 3+) on EZH2 phosphorylation and the signaling pathways important for As 
( 3+) -induced EZH2 phosphorylation in human bronchial epithelial cell line 
BEAS-2B. The involvement of kinases in As ( 3+) -induced EZH2 phosphorylation 
was validated by siRNA-based gene silencing. The data showed that As ( 3+) can 
induce phosphorylation of EZH2 at serine 21 in human bronchial epithelial cells 
and that the phosphorylation of EZH2 requires an As ( 3+) -activated signaling 
cascade from JNK and STAT3 to Akt. Transfection of the cells with siRNA specific 
for JNK1 revealed that JNK silencing reduced serine727 phosphorylation of STAT3, 
Akt activation and EZH2 phosphorylation, suggesting that JNK is the upstream 
kinase involved in As ( 3+) -induced EZH2 phosphorylation. Because As ( 3+) is 
capable of inducing miRNA-21 (miR-21), a STAT3-regulated miRNA that represses 
protein translation of PTEN or Spry2, we also tested the role of STAT3 and 
miR-21 in As ( 3+) -induced EZH2 phosphorylation. Ectopic overexpression of 
miR-21 promoted Akt activation and phosphorylation of EZH2, whereas inhibiting 
miR-21 by transfecting the cells with anti-miR-21 inhibited Akt activation and 
EZH2 phosphorylation. Taken together, these results demonstrate a contribution 
of the JNK, STAT3 and Akt signaling axis to As ( 3+) -induced EZH2 
phosphorylation. Importantly, these findings may reveal new molecular mechanisms 
underlying As ( 3+) -induced carcinogenesis.