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Arsenic promotes ROS-mediated malignant transformation of bronchial epithelial cells by specifically downregulating
Lingling Zhao1, Xueli Jiao2,3, Hongyan Li2
1Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. zhaolingling@wmu.edu.cn.
Abstract:
Arsenic exposure is a known cause of lung cancer, primarily mediated through reactive oxygen species (ROS) generation and oxidative DNA damage. However, the precise mechanism by which arsenic modulates ROS levels remains unclear. This study reveals that, contrary to the upregulation of various key ROS scavenging genes, arsenic specifically downregulates the expression of the redox-active protein thioredoxin-like 1 (TXNL1) both in vitro and in vivo. Enhancing TXNL1 expression significantly suppresses arsenic-induced ROS production, DNA oxidative damage, and malignant transformation. Mechanistic investigations indicate that arsenic downregulates TXNL1 expression through the downregulation of the deubiquitinase USP10, which leads to increased ubiquitination and degradation of TXNL1. Additionally, arsenic promotes hypermethylation of the USP10 promoter region by upregulating the expression of DNA methyltransferase 1 (DNMT1), resulting in transcriptional repression of USP10. In summary, our results reveal that arsenic disrupts redox homeostasis via the DNMT1-USP10-TXNL1 axis, identifying a potential target for preventing arsenic-induced lung carcinogenesis.
Insights
Arsenic exposure downregulates thioredoxin-like 1 (TXNL1) by affecting USP10 and DNMT1, increasing lung cancer risk. Restoring TXNL1 may prevent arsenic-induced cancer.
Area of Science:
- Environmental Health
- Molecular Biology
- Cancer Research
Background:
- Arsenic exposure is a known lung carcinogen, linked to reactive oxygen species (ROS) and DNA damage.
- The exact mechanisms by which arsenic influences ROS levels are not fully understood.
Purpose of the Study:
- To elucidate the role of thioredoxin-like 1 (TXNL1) in arsenic-induced lung carcinogenesis.
- To investigate the molecular pathways through which arsenic affects TXNL1 expression and redox homeostasis.
Main Methods:
- In vitro and in vivo studies to assess TXNL1 expression.
- Investigating the impact of TXNL1 enhancement on arsenic-induced cellular changes.
- Analyzing the roles of USP10 and DNMT1 in arsenic's effect on TXNL1.
Main Results:
- Arsenic downregulates TXNL1 expression, contrary to other ROS scavenging genes.
- Increased TXNL1 suppresses arsenic-induced ROS, DNA damage, and malignant transformation.
- Arsenic downregulates USP10, leading to TXNL1 degradation, and upregulates DNMT1, causing USP10 promoter hypermethylation.
Conclusions:
- Arsenic disrupts redox homeostasis through the DNMT1-USP10-TXNL1 pathway.
- This pathway represents a potential therapeutic target for preventing arsenic-induced lung cancer.
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