Inhibition of monomethylarsonous acid (MMAIII)-induced cell malignant transformation through restoring dysregulated histone acetylation

Inorganic arsenic (iAs) and its high toxic metabolite, monomethylarsonous acid (MMAIII), are able to induce malignant transformation of human cells. Chronic exposure to these chemicals is associated with an increased risk of developing multiple cancers in human. However, the mechanisms contributing to iAs/MMAIII-induced cell malignant transformation and carcinogenesis are not fully elucidated. We recently showed that iAs/MMAIII exposure to human cells led to a decreased level of histone acetylation globally, which was associated with an increased sensitivity to arsenic cytotoxicity. In the current study, it demonstrated that prolonged exposure to low-level MMAIII in human urothelial cells significantly increased the expression and activity of histone deacetylases (HDACs) with an associated reduction of histone acetylation levels both globally and lysine specifically. Administration of the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), at 4 weeks after the initial MMAIII treatment inhibited the MMAIII-mediated up-regulation of the expression and activities of HDACs, leading to increase histone acetylation and prevention of MMAIII-induced malignant transformation. These new findings suggest that histone acetylation dysregulation may be a key mechanism in MMAIII-induced malignant transformation and carcinogenesis, and that HDAC inhibitors could be targeted to prevent or treat iAs-related cancers.