Inorganic arsenic‐mediated upregulation of AS3MT promotes proliferation of nonsmall cell lung cancer cells by regulating cell cycle genes

Abstract

Long‐term arsenic exposure can promote cancer through epigenetic mechanisms, and arsenite methyltransferase (AS3MT) plays an important role in this process. However, the expression patterns and mechanisms of AS3MT in arsenic carcinogenesis remain unclear. In this study, we found that the AS3MT was overexpressed in arsenic exposed population, non‐small cell lung cancer (NSCLC) tissues, and A549 cells with sodium arsenite (NaAsO2) treatment for 48 hours. Besides, the level of AS3MT expression was positively correlated with the concentrations of urinary total arsenic (tAs), inorganic arsenic (iAs), methanearsonic acid (MMA), and dimethylarsinic acid (DMA) in all subjects. Functional experiments demonstrated that siRNA‐mediated knockdown of AS3MT significantly inhibited proliferation of A549 cells. Mechanism investigation revealed that silencing of AS3MT inhibited proliferation by increasing mRNA expression levels of p21 and E2F1, and inhibiting CDK1, CDK2, CDK4, CDK6, Cyclin A2, Cyclin E1, Cyclin E2, and PCNA mRNA expression. Therefore, arsenic increased AS3MT expression in vivo and in vitro, which could directly act on the cell and affect the progression of NSCLC by regulating cell cycle genes.

Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications

“…The carcinogenic potential of arsenic is attributed to genotoxicity and to disturbances of epigenetic mechanisms [234,235]. Despite the abundant literature on the toxicity of arsenic [273][274][275] and the existing regulatory measures taken by numerous agencies (e.g., maximum drinking water contamination level of 10 µg/L (10 ppb or 0.13 µM) set by the World Health Organization and US-EPA [276]), the toxicity of this metal is still an important risk assessment research topic. This is because: (1) it is present naturally in the environment and as waste in mining industries [277], (2) inorganic arsenic levels exceed safe limits in drinking water in more than 50 countries [278], (3) reasons for interindividual disease susceptibility to arsenic must be understood [278], (4) mitigation [278] or remediation nutritional supports are required for the exposed population [273], and (5), understanding the extent of genotoxic and non-genotoxic mechanisms contributing to its carcinogenic mode of action is important given that this might influence regulatory measures and treatment intervention for correctable non-genotoxic epigenetic anomalies.…”

The RNA N6‐methyladenosine modulator HNRNPA2B1 is involved in the development of non‐small cell lung cancer

“…5,6 Targeted therapy is also an effective method for individualized NSCLC treatment. [7][8][9] Recently, the programmed cell death protein-1 (PD-1) and the antibody for PD-L1 represent a new strategy for NSCLC patients. [10][11][12] Nevertheless, therapy for NSCLC is still unsatisfactory.…”

The Novel Role of Arsenic (+3 oxidation state) Methyltransferase in Arsenic Genotoxicity

“…In previous study, AS3MT mRNA was over expressed in lung cancer patients who have not exposed to arsenic (28). How AS3MT induced by arsenic could directly act on the cell and affect tumorigenesis and progression need to study.…”

“…P21 is a negative regulator of the cell cycle, as p53 binds to the p21 promoter and activates its transcription, which inhibit DNA replication and impede entry into mitosis by binding to PCNA (31,32). However, previous research revealed that PCNA and CDKs were signi cantly low expression in siAS3MT groups (28). So, it been speculated that AS3MT is involved in regulation p53/p21 axis, and promote cell proliferation.…”