ALKBH5 and nickel-induced lung carcinogenesis

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Project Summary Nickel compounds are well-established human carcinogens. Epidemiological studies have reported an increased incidence of lung and nasal cancer following long-term exposure to nickel compounds due to either environmental or occupational exposure. Growing evidence indicates that alterations of the epigenetic landscape, including DNA methylation and histone modification, are important mechanisms in nickel-induced lung carcinogenesis. However, the impact of nickel exposure on the epitranscriptome and the potential role of RNA modification in nickel carcinogenesis have never been explored. Our preliminary studies discovered that human bronchial epithelial cells exposed to nickel compounds exhibited reduced mRNA stability of maternally expressed gene 3 (MEG3), an imprinted gene that was downregulated in many types of tumors and a strong driver for nickel-induced malignant transformation. In addition, nickel upregulated m6A demethylase ALKBH5 mRNA and protein expression that coincided with MEG3 RNA destabilization, suggesting ALKBH5 may contribute to cell transformation via modulating global- or gene-specific m6A abundance. Moreover, knockdown of ALKBH5 completely abolished MEG3 degradation in nickel-exposed cells, suggesting that RNA methylation may play a role in protecting MEG3 stability. However, it is not clear how nickel upregulates ALKBH5 as well as whether increased ALKBH5 mediates nickel-induced cell transformation. Additionally, how m6A abundance modulates MEG3 RNA stability remains largely unknown. Therefore, in this application, two specific aims were proposed to address the key events in nickel-induced MEG3 destabilization. The first aim will address whether increased ALKBH5 is sufficient to induce malignant transformation in vitro. The second aim will target the potential upstream regulators and downstream effectors that mediate nickel-induced ALKBH5 expression and MEG3 destabilization. To the best of our knowledge, this is the first proposal to tackle the impact of environmental nickel exposure on the changes of m6A enzymes as well as transcriptome-wide or gene-specific m6A methylation profiles. Success of this proposal will facilitate our understanding of how nickel targets RNA modification enzymes or RNA binding proteins to initiate or promote lung tumor formation, and further identify new aspects of m6A enzymes as a prognostic biomarkers or therapeutic targets to improve clinical outcomes of lung cancer patients.