Ring Finger Protein 1, a Novel Ubiquitin E3 Ligase Targeting Cancerous Inhibitor of Protein Phosphatase 2A to Suppress Smoking‐Induced Lung Tumorigenesis

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that promotes cancer cell proliferation, invasion, and drug resistance. In this study, CIP2A expression was found to be higher in lung cancer tissues compared to adjacent normal tissues. Knocking down CIP2A in lung cancer cells reduced cell proliferation and migration. Ring finger protein 1 (RING1), a member of the RING family in the ubiquitin-proteasome system, was identified as a potential E3 ligase for CIP2A. The interaction between RING1 and CIP2A was confirmed, with RING1 regulating CIP2A ubiquitination. Knockdown of RING1 increased lung cancer cell proliferation and migration in vitro and in vivo, linked to the upregulation of CIP2A and its downstream molecules, c-MYC and Cyclin B1. Smoking's impact on RING1 expression was examined using cigarette smoke extract (CSE), which decreased RING1 mRNA and protein levels. This led to CIP2A and c-MYC upregulation. The carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a constituent of CSE, downregulated RING1 expression through DNA methyltransferase 1 (DNMT1) activation, whereas inhibition of DNMT1 restored RING1 levels. These findings highlight the DNMT1-RING1-CIP2A axis in lung cancer progression due to smoking and suggest potential therapeutic and diagnostic targets.