Roles of transcription factors AHR, ZEB1 and SNAI1 in deregulation of SL and GSL metabolism during epithelial-to-mesenchymal transition in human bronchial cells

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00027162%3A_____%2F24%3AN0000180" target="_blank" >RIV/00027162:_____/24:N0000180 - isvavai.cz</a>

Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Roles of transcription factors AHR, ZEB1 and SNAI1 in deregulation of SL and GSL metabolism during epithelial-to-mesenchymal transition in human bronchial cells

Popis výsledku v původním jazyce

The alterations of expression of genes linked to sphingolipid (SL) and glycosphingolipid (GSL) metabolism and changes in sphingolipidomic profiles during cancer development and progression still remain only partially characterized. Here, we evaluated potential roles of three transcription factors contributing to deregulation of SL/GSL metabolism occurring during epithelial-to-mesenchymal transition (EMT) of normal bronchial epithelial cells HBEC-12KT, which was induced by a chronic exposure to environmental carcinogen benzo[a]pyrene (BaP). The aryl hydrocarbon receptor (AHR) is a transcription factor well-known for its roles in xenobiotic metabolism; however, it may also belong among important regulators of endogenous lipid metabolism and tumor development. ZEB1 and SNAI1 are two transcriptional regulators of EMT, which help to maintain mesenchymal status of tumor cells. RESULTS. When modulating chemically the AHR transcriptional activity in wild type HBEC-12KT cell line, we observed upregulation of sphingosin-1-phosphate and glucosylceramides after AHR activation, which may contribute to the induction of early phase of EMT by BaP. Using siRNA-mediated silencing of ZEB1 or SNAI1 we observed significant modulations of SL/GSL gene expression and SL/GSL metabolism in the BaP-transformed mesenchymal-like HBEC-12KT-B1 cells. The ZEB1 knockdown significantly altered expression of SPHK2, SGPL1, GBA2, B4GALT5, B4GALT6, ST8SIA4, B4GALNT1, A4GALT, HEXA, HEXB and several other genes, accompanied with significant changes in SL and GSL levels. The SNAI1 knockdown indicated that this transcription factor may support increased biosynthesis of several SL species, including sphingosine-1-phosphate and sphingosine, and it had a partial impact on control of GM and GD synthesis pathways. The CERK, B4GALT5, ST3GAL5, ST8SIA5 and A4GALT were among the most deregulated genes in cells with silenced SNAI1. CONCLUSIONS. While the AHR may contribute to the changes in SL/GSLs during early stages of EMT, both ZEB1 and SNAI1 seem to play important, and partly complementary, roles in deregulation of a series of genes related to SL/GSL metabolism in fully transformed mesenchymal-like HBEC-12KT-B1 cells. Deregulation of SL and GSL metabolism plays various functional roles in diseases including carcinogenesis and malignant tumor progression. The present data indicate the need to further explore the mechanisms regulating SL/GSL levels and functions.

Název v anglickém jazyce

Roles of transcription factors AHR, ZEB1 and SNAI1 in deregulation of SL and GSL metabolism during epithelial-to-mesenchymal transition in human bronchial cells

Popis výsledku anglicky

The alterations of expression of genes linked to sphingolipid (SL) and glycosphingolipid (GSL) metabolism and changes in sphingolipidomic profiles during cancer development and progression still remain only partially characterized. Here, we evaluated potential roles of three transcription factors contributing to deregulation of SL/GSL metabolism occurring during epithelial-to-mesenchymal transition (EMT) of normal bronchial epithelial cells HBEC-12KT, which was induced by a chronic exposure to environmental carcinogen benzo[a]pyrene (BaP). The aryl hydrocarbon receptor (AHR) is a transcription factor well-known for its roles in xenobiotic metabolism; however, it may also belong among important regulators of endogenous lipid metabolism and tumor development. ZEB1 and SNAI1 are two transcriptional regulators of EMT, which help to maintain mesenchymal status of tumor cells. RESULTS. When modulating chemically the AHR transcriptional activity in wild type HBEC-12KT cell line, we observed upregulation of sphingosin-1-phosphate and glucosylceramides after AHR activation, which may contribute to the induction of early phase of EMT by BaP. Using siRNA-mediated silencing of ZEB1 or SNAI1 we observed significant modulations of SL/GSL gene expression and SL/GSL metabolism in the BaP-transformed mesenchymal-like HBEC-12KT-B1 cells. The ZEB1 knockdown significantly altered expression of SPHK2, SGPL1, GBA2, B4GALT5, B4GALT6, ST8SIA4, B4GALNT1, A4GALT, HEXA, HEXB and several other genes, accompanied with significant changes in SL and GSL levels. The SNAI1 knockdown indicated that this transcription factor may support increased biosynthesis of several SL species, including sphingosine-1-phosphate and sphingosine, and it had a partial impact on control of GM and GD synthesis pathways. The CERK, B4GALT5, ST3GAL5, ST8SIA5 and A4GALT were among the most deregulated genes in cells with silenced SNAI1. CONCLUSIONS. While the AHR may contribute to the changes in SL/GSLs during early stages of EMT, both ZEB1 and SNAI1 seem to play important, and partly complementary, roles in deregulation of a series of genes related to SL/GSL metabolism in fully transformed mesenchymal-like HBEC-12KT-B1 cells. Deregulation of SL and GSL metabolism plays various functional roles in diseases including carcinogenesis and malignant tumor progression. The present data indicate the need to further explore the mechanisms regulating SL/GSL levels and functions.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30108 - Toxicology

Projekt

<a href="/cs/project/GA24-10086S" target="_blank" >GA24-10086S: Dopady působení polycyklických aromatických uhlovodíků na buněčné procesy spojené se stresovou signalizací a deregulací metabolismu</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů