Abstract 879: Nicotine-induced oxidative stress causes epigenetic alterations during malignant transformation of human kidney epithelial cells

Nicotine is a component of cigarette smoke and mounting evidence implicates tobacco smoking in kidney cancer development. Whether nicotine alone can cause kidney cancer is not clear. Moreover, the underlying molecular mechanisms for nicotine-induced carcinogenesis is still not well-understood. Therefore, the objective of this study was to determine if chronic exposure to nicotine results in malignant transformation of HK-2 kidney epithelial cells. The data revealed that chronic exposure to nicotine induced growth and malignant transformation in HK-2 cells. Additionally, the nicotine-exposed cells had inherently increased levels of intracellular ROS, and acquired stem cell-like sphere formation, as well as epithelial-mesenchymal-transition (EMT) changes during malignant transformation. Treatment with antioxidant NAC resulted in abrogation of EMT and stem cell-like sphere in HK-2 cells, suggesting the role of nicotine-induced ROS in these morphological changes. Additionally, epigenetic reagents 5-aza-2'-deoxycytidine and trichostatin A also diminished stem cell-like sphere in nicotine-exposed HK-2 cells. The nicotine also induced changes in the expression of epigenetic genes (DNMT3a, DNMT3b, and HMT1) and these changes were reversed by NAC treatment. This further supports the role of nicotine-induced ROS in epigenetic changes during malignant transformation of HK-2 cells. The altered levels of pAKT in low dose nicotine exposed cells were restored after NAC treatment, suggesting that nicotine-induced ROS, through regulation of AKT pathway, controls the EMT and stemness during early stages of carcinogenesis. In summary, to our knowledge, this is the first report showing that chronic exposure to nicotine induces malignant transformation in human kidney epithelial cells through ROS-mediated epigenetic modifications.

Citation Format: Yuwei Chang, Kamaleshwar Singh. Nicotine-induced oxidative stress causes epigenetic alterations during malignant transformation of human kidney epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 879.