Transcription factor SP1 and oncoprotein PPP1R13L regulate nicotine-induced epithelial-mesenchymal transition in lung adenocarcinoma via a feedback loop

Hongchao Zhang; Guopei Zhang; Jingyue Zhang; Mingyang Xiao; Su Cui; Shengwen Wu; Cuihong Jin; Jinghua Yang; Xiaobo Lu

doi:10.1016/j.bcp.2022.115344

Transcription factor SP1 and oncoprotein PPP1R13L regulate nicotine-induced epithelial-mesenchymal transition in lung adenocarcinoma via a feedback loop

Biochem Pharmacol. 2022 Dec:206:115344. doi: 10.1016/j.bcp.2022.115344. Epub 2022 Nov 11.

Authors

Hongchao Zhang¹, Guopei Zhang¹, Jingyue Zhang¹, Mingyang Xiao¹, Su Cui², Shengwen Wu¹, Cuihong Jin¹, Jinghua Yang¹, Xiaobo Lu³

Affiliations

¹ Department of Toxicology, School of Public Health, China Medical University, Shenyang 110122, People's Republic of China.
² Department of Thoracic Surgery Ward 2, The First Hospital of China Medical University, Shenyang 110002, People's Republic of China.
³ Department of Toxicology, School of Public Health, China Medical University, Shenyang 110122, People's Republic of China. Electronic address: xblu@cmu.edu.cn.

PMID: 36372331
DOI: 10.1016/j.bcp.2022.115344

Abstract

Tobacco remains the most common environmental carcinogen leading to the occurrence and development of lung cancer. Nicotine, a tumor promoter in cigarette smoke, has been shown to induce epithelial-mesenchymal transition (EMT), a cellular program required for the invasion and metastasis in tumor cells. Specificity Protein 1 (SP1) is a well-characterized transcription factor that can regulate the EMT process via transcriptionally activating E-cadherin expression. Protein Phosphatase 1 Regulatory Subunit 13 Like (PPP1R13L) is a newly identified oncoprotein previously reported to inhibit the transcriptional activity of SP1 via a direct protein-protein interaction. To reveal the underlying implication of the interconnections between PPP1R13L and SP1 in the nicotine-induced EMT process, the present study established an EMT cell model of lung cancer using 1 μM of nicotine, a dose close to human exposure, in which an alternate fluctuation in the expression of PPP1R13L and SP1 was captured. Subsequently, the direct inhibition of SP1 by PPP1R13L was demonstrated to be a critical mechanism underlying the involvement of PPP1R13L in the nicotine-induced EMT process. More interestingly, SP1 was further shown to transcriptionally activate PPP1R13L expression in a feedback manner. In addition, PPP1R13L and SP1 expression was found to be closely associated with the clinicopathological characteristics of lung cancer patients. Here we proposed a novel feedback regulation mechanism, in which SP1 may transcriptionally activate the PPP1R13L gene expression in the early stage of lung cancer to promote tumor growth, while the accumulation of PPP1R13L drives tumor invasion and metastasis by direct repression of SP1. Thus, this unique feedback loop between PPP1R13L and SP1 may play a vital role in chemical carcinogenesis and serve as a potential intervention target for lung cancer progression attributable to cigarette smoking.

Keywords: Epithelial-mesenchymal transition (EMT); Feedback regulation; Lung cancer; Nicotine; PPP1R13L; SP1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma of Lung* / genetics
Cell Line, Tumor
Cell Movement
Epithelial-Mesenchymal Transition
Feedback
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms* / chemically induced
Lung Neoplasms* / genetics
Lung Neoplasms* / metabolism
Nicotine / toxicity
Oncogene Proteins / metabolism
Protein Phosphatase 1 / genetics
Protein Phosphatase 1 / metabolism
Repressor Proteins / metabolism
Sp1 Transcription Factor
Transcription Factors / metabolism

Substances

Nicotine
Protein Phosphatase 1
Transcription Factors
Oncogene Proteins
Sp1 Transcription Factor
SP1 protein, human
PPP1R13L protein, human
Repressor Proteins