Cotinine Promotes Cancer Cell Proliferation and m1A RNA Methylation in Smoking-Associated Lung Cancer by Targeting PLK1/β-Catenin/TRMT6 Axis.

Nicotine is the most abundant alkaloid in tobacco, and 70%-80% of its metabolites are cotinine. In terms of that, numerous cigarettes are consumed worldwide, resulting in a large amount of cotinine being released into the environment and posing potential hazards. However, the biological effects of cotinine are poorly understood. In the current study, we identified that the oncogene Polo-like kinase 1 (PLK1) is a direct target of cotinine, and cotinine could upregulate the protein level of PLK1. Public epidemiological data indicated a positive correlation between PLK1 expression and smoking. Subsequent studies validated that PLK1 directly interacted with β-catenin, leading to transcriptional activation of tRNA methyltransferase 6 (TRMT6), a canonical methyltransferase involved in m1A methylation modification of RNA. Dot blot showed that cotinine enhanced m1A RNA methylation in lung cancer cells. Public epidemiological data also demonstrated a positive correlation between the expression of TRMT6 and smoking. Knockdown of TRMT6 impaired cell proliferation and sensitized lung cancer cells to common chemotherapeutic agents. Taken together, our current study indicated a previously unknown role of cotinine in promoting cancer cell proliferation by targeting the PLK1/β-catenin/TRMT6 axis, which may shed light on the connection between smoking and RNA modifications.