Hexavalent chromium [Cr(VI)] is a common environmental carcinogen causing lung cancer in humans. This study investigates the mechanism of Cr(VI) carcinogenesis focusing on the role of the epitranscriptomic dysregulation. The epitranscriptomic effect of Cr(VI) was determined in Cr(VI)-transformed human bronchial epithelial cells, chromate-exposed mouse and human lungs. The epitranscriptomic effect and its role in Cr(VI)-induced cell transformation, cancer stem cell (CSC)-like property, and tumorigenesis were determined by microarray analysis, soft agar colony formation, suspension spheroid formation, and mouse xenograft tumorigenesis assays. It was found that chronic Cr(VI) exposure causes epitranscriptomic dysregulations as evidenced by the increased levels of total RNA N6-methyladenosine (m6A) modification and the RNA m6A methyltransferase like-3 (METTL3) in Cr(VI)-transformed cells and chromate exposure-caused mouse and human lung tumors. Knockdown of METTL3 expression in Cr(VI)-transformed cells significantly reduces their m6A levels and transformed phenotypes and tumorigenicity in mice. Moreover, knockdown of METTL3 expression in parental nontransformed cells significantly reduces the capability of chronic Cr(VI) exposure to induce cell transformation and CSC-like property. Together, this study reveals that chronic Cr(VI) exposure is capable of altering cellular epitranscriptome by increasing the m6A RNA modification via upregulating the RNA methyltransferase METTL3 expression, which plays an important role in Cr(VI)-induced cell transformation, CSC-like property, and tumorigenesis.
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http://dx.doi.org/10.1093/toxsci/kfac023 | DOI Listing |
J Cell Mol Med
January 2025
Zhengzhou Key Laboratory of Cardiovascular Aging, Henan Province Key Laboratory for Prevention and Treatment of Coronary Heart Disease, National Health Commission key Laboratory of Cardiovascular Regenerative Medicine, Central China Fuwai Hospital of Zhengzhou University, Fuwai Central China Cardiovascular Hospital & Central China Branch of National Center for Cardiovascular Diseases, Zhengzhou, Henan, China.
N6-adenosine methylation (m6A) of RNA is involved in the regulation of various diseases. However, its role in chemotherapy-related vascular endothelial injury has not yet been elucidated. We found that methyltransferase-like 3 (METTL3) expression was significantly reduced during doxorubicin (DOX)-induced apoptosis of vascular endothelial cells both in vivo and in vitro, and that silencing of METTL3 further intensified this process.
View Article and Find Full Text PDFBackground: N6-methyladenosine (m6A) methylation plays a key role in tumor progression. However, the significance of methyltransferase-like 3 (METTL3) in biological processes of soft tissue sarcoma (STS) patients, and the relationship between METTL3 and STS are unclear.
Methods: The expression of METTL3 in STS and its relationship with patient prognosis were determined from database analyses.
Nat Neurosci
January 2025
Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA.
Huntington's disease (HD) is caused by a CAG repeat expansion in the HTT gene, leading to altered gene expression. However, the mechanisms leading to disrupted RNA processing in HD remain unclear. Here we identify TDP-43 and the N6-methyladenosine (m6A) writer protein METTL3 to be upstream regulators of exon skipping in multiple HD systems.
View Article and Find Full Text PDFJ Mol Cell Biol
January 2025
Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
The development and homeostasis of intestinal epithelium are mediated by actively proliferating Lgr5+ stem cells, which possess a remarkable self-renewal and differentiation capacity. Recently, our study demonstrated that m6A methylation was essential for the survival of colonic stem cells. Here, we show that METTL3 expression is downregulated in the colon mucosa in ulcerative colitis (UC) patients and strongly associated with the differentiation and maturation of goblet cells during inflammation.
View Article and Find Full Text PDFGene
January 2025
Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Object: N6-methyladenosine (mA), is well known as the most abundant epigenetic modification in messenger RNA, but its influence on laryngeal squamous cell carcinoma (LSCC) remains largely unexplored and poorly understood. This study was designed to explore the effects of mA on WISP1-mediated epithelial-mesenchymal transition (EMT) and tumorigenesis in LSCC.
Methods: mA methylated and expression levels of WISP1 in LSCC tumor tissues and cells were measured by MeRIP-qPCR, qRT-PCR, and western blotting.
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