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

Abstract

AbstractInorganic 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.