1. Academic Validation
  2. Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1

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

  • J Appl Toxicol. 2023 Mar 1. doi: 10.1002/jat.4457.
Jiafeng Chen 1 2 Cece Lei 1 2 Daibang Nie 1 2 Huan Ge 3 Jian Li 3 Changbin Lei 3 4 Wang Wang 1 2
Affiliations

Affiliations

  • 1 Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, China.
  • 2 Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, Chongqing Medical University, Chongqing, China.
  • 3 Department of Orthopedics, Affiliated Hospital of Xiangnan University, Chenzhou, China.
  • 4 Heavy metal pollution and cancer prevention Technology Research Center, Chenzhou, China.
Abstract

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 due to the known hormesis effect of arsenic. Here, we established that 6-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 a combination with chemotherapeutic agent. These findings provide valuable information for understanding the mechanisms of arsenic-induced carcinogenesis and facilitating the health management for populations in arsenic-polluted areas.

Keywords

HDAC6; HTRA1; Inorganic arsenic; cancer; intestine.

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