Cigarette smoke modulates binding of the transcription factor MZF1 to the VEGF promoter and regulates VEGF expression in dependence of genetic variation SNP 405

Abstract

Background Vascular endothelial growth factor (VEGF) affects carcinogenesis of the upper aerodigestive tract. Cigarette smoke (CSE) influences VEGF‐gene regulation. The single nucleotide polymorphism +405 G/C (SNP +405 G/C) and the transcriptional factor (TF) myeloid zinc finger 1 (MZF1) are endogenic regulators of the VEGFpromoter as the polymorphism 405 potentially affects binding of the transcription factor MZF1. Therefore, this in vitro study analysed cancer cells of the upper aerodigestive tract after CSE incubation concerning MZF1‐binding specificity and VEGF expression in dependency of VEGF polymorphism +405 G/C compared to wild type (wt). Methods In human alveolar epithelial‐like type‐II cells (A549) and oral squamous cell cancer cells (HNSCCUM‐02T) SNP +405 G/C‐ and MZF1‐dependent VEGF promoter activity and VEGF expression were analysed by qRT‐PCR and Western blot after incubation with 10% CSE. Temporary knock‐down of MZF1 was performed using siRNA. MZF1 binding was analysed by Co‐Chromatin‐Immunoprecipitation (Co‐ChiP) (each test n = 3). Results We found a stronger MZF1 binding to VEGF polymorphism 405 in A549 cells (P < .05) compared to HNSCCUM‐02T cells (P = .02), where MZF1 binding was reduced. MZF1 knock out reduced VEGF promoter activity in HNSCCUM‐02T cells, showing the relevance of the factor for transcriptional activation of the VEGF promoter. Finally, we found that CSE increases promoter activity in both cell lines and no significant differences between the two analysed polymorphisms concerning their activating capacity. Conclusion In summary, both VEGF promoter polymorphisms are similar effective in terms of transcriptional activity, and MZF1 is a transcriptional activator of VEGF promoter. Moreover, cigarette smoke increases MZF1 binding of VEGF‐promoter and directly affects VEGF‐gene regulation.

SCAND1 Reverses Epithelial-to-Mesenchymal Transition (EMT) and Suppresses Prostate Cancer Growth and Migration

“…However, MZF1 can also function as a tumor suppressor that, for instance, represses MMP2 in cervical cancer [ 34 ] and mediates oncogene-induced senescence [ 35 ]. Furthermore, MZF1 is also vital in a protumorigenic microenvironment by activating the osteopontin ( OPN ) gene in mesenchymal stem cells (MSC), leading to transformation into cancer-associated fibroblasts (CAF) [ 36 ] and the VEGF gene in tumor endothelial cells (TEC) [ 37 ].…”

Cigarette smoking combined with genetic variation regulates the m6A methylation of CRNKL1 and is associated with bladder cancer risk

“…Additionally, our previous findings have shown that cigarette smoking combine with genetic variations to jointly affect bladder cancer risk 8 . Importantly, cigarette smoking and genetic variant can collaboratively regulate downstream gene expression by influencing transcription factor binding and DNA methylation 36,37 . Our findings have now revealed that the combination of cigarette smoking and rs2273058 may also regulate CRNKL1 expression through m 6 A modification and its recognition.…”

“…8 Importantly, cigarette smoking and genetic variant can collaboratively regulate downstream gene expression by influencing transcription factor binding and DNA methylation. 36,37 Our findings have now revealed that the combination of cigarette smoking and rs2273058 may also regulate CRNKL1 expression through m 6 A modification and its recognition. Therefore, our study contributes to the existing knowledge about how cigarette smoking interacts with genetic factors to affect bladder disease risk.…”

SCAND1 Reverts EMT and Suppresses Tumor Growth and Collective Migration

“…However, MZF1 can also function as a tumor suppressor that, for instance represses MMP2 in cervical cancer [34] and mediates oncogene-induce senescence [35]. Furthermore, MZF1 is also important in a protumorigenic microenvironment by activating osteopontin gene in mesenchymal stem cells, leading to transformation into cancer-associated fibroblasts (CAF) [36] and VEGF gene in tumor endothelial cells [37].…”