Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1

Inorganic arsenic (iAs) has been a human health concern and is associated with intestinal malignancies. However, the molecular mechanisms of the iAs-induced oncogenic process in intestine epithelial cells remain elusive, partly because of the known hormesis effect of arsenic. Here, we established that six-month exposure to iAs at a concentration similar to those found in contaminated drinking water could promote malignant characteristics, including enhanced proliferation and migration, resistance to apoptosis, and mesenchymal-like transition in Caco-2 cells. Transcriptome analysis and mechanism study revealed that key genes and pathways involved in cell adhesion, inflammation and oncogenic regulation were altered during chronic iAs exposure. Specifically, we uncovered that down-regulation of HTRA1 was essential for the iAs-induced acquisition of the cancer hallmarks. Further, we evidenced that the loss of HTRA1 during iAs-exposure could be restored by HDAC6 inhibition. Caco-2 cells with chronic exposure to iAs exhibited enhanced sensitivity to WT-161, a specific inhibitor of HDAC6, when used alone than in combination with a chemotherapeutic agent. These findings provide valuable information for understanding the mechanisms of arsenic-induced carcinogenesis and facilitating the health management of populations in arsenic-polluted areas.