Nicotine-derived NNK promotes CRC progression through activating TMUB1/AKT pathway in METTL14/YTHDF2-mediated m6A manner.

Cigarette smoking substantially promotes tumorigenesis and progression of colorectal cancer; however, the underlying molecular mechanism remains unclear. Among 662 colorectal cancer patients, our investigation revealed a significant correlation between cigarette smoking and factors, such as large tumor size, poor differentiation, and high degree of invasion. Among the nicotine-derived nitrosamines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) emerged as the most critical carcinogen, which significantly promoted the malignant progression of colorectal cancer both in vivo and in vitro. The results of methylated RNA immunoprecipitation and transcriptome sequencing indicated that NNK upregulated transmembrane and ubiquitin-like domain-containing protein 1 (TMUB1) via N6-adenosine methylation, which was regulated by methyltransferase-like 14 (METTL14) and YTH N6-methyladenosine RNA binding protein 2 (YTHDF2). Elevated TMUB1 levels were associated with a higher risk of cancer invasion and metastasis, leading to a high mortality risk in patients with colorectal cancer. Additionally, TMUB1 promoted lysine63-linked ubiquitination of AKT by interacting with AMFR, which led to the induction of malignant proliferation and metastasis in colorectal cancer cells exposed to NNK. In summary, this study provides a new insight, indicating that targeting TMUB1 expression via METTL14/YTHDF2 mediated N6-adenosine methylation may be a potential therapeutic and prognostic target for patients with colorectal cancer who smoke.