TPH1 and 5-HT<sub>7</sub> Receptor Overexpression Leading to Gemcitabine-Resistance Requires Non-Canonical Permissive Action of EZH2 in Pancreatic Ductal Adenocarcinoma

In the present study, we investigated the regulatory mechanisms underlying overexpression of EZH2, tryptophan hydroxylase 1 (TPH1), and 5-HT<sub>7</sub>, in relation to gemcitabine resistance and CSC survival in PDAC cells. In aggressive PANC-1 and MIA PaCa-2 cells, knock-down (KD) of EZ...

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Autores principales:	Prakash Chaudhary, Diwakar Guragain, Jae-Hoon Chang, Jung-Ae Kim
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	pancreatic ductal adenocarcinoma gemcitabine-resistance cancer stem cells Enhancer of zeste homolog 2 tryptophan hydroxylase 1 5-HT<sub>7</sub> Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/02cdd7aa1b8f41acb4e0f8e272d84f6e
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spelling	oai:doaj.org-article:02cdd7aa1b8f41acb4e0f8e272d84f6e2021-11-11T15:27:52ZTPH1 and 5-HT<sub>7</sub> Receptor Overexpression Leading to Gemcitabine-Resistance Requires Non-Canonical Permissive Action of EZH2 in Pancreatic Ductal Adenocarcinoma10.3390/cancers132153052072-6694https://doaj.org/article/02cdd7aa1b8f41acb4e0f8e272d84f6e2021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5305https://doaj.org/toc/2072-6694In the present study, we investigated the regulatory mechanisms underlying overexpression of EZH2, tryptophan hydroxylase 1 (TPH1), and 5-HT<sub>7</sub>, in relation to gemcitabine resistance and CSC survival in PDAC cells. In aggressive PANC-1 and MIA PaCa-2 cells, knock-down (KD) of EZH2, TPH1, or HTR7 induced a decrease in CSCs and recovery from gemcitabine resistance, while preconditioning of less aggressive Capan-1 cells with 5-HT induced gemcitabine resistance with increased expression of EZH2, TPH1, and 5-HT<sub>7</sub>. Such effects of the gene KD and 5-HT treatment were mediated through PI3K/Akt and JAK2/STAT3 signaling pathways. EZH2 KD or GSK-126 (an EZH2 inhibitor) inhibited activities of these signaling pathways which altered nuclear level of NF-kB, Sp1, and p-STAT3, accompanied by downregulation of TPH1 and 5-HT<sub>7</sub>. Co-immunoprecipation with EZH2 and pan-methyl lysine antibodies revealed that auto-methylated EZH2 served as a scaffold for binding with methylated NF-kB and Sp1 as well as unmethylated p-STAT3. Furthermore, the inhibitor of EZH2, TPH1, or 5-HT<sub>7</sub> effectively regressed pancreatic tumor growth in a xenografted mouse tumor model. Overall, the results revealed that long-term exposure to 5-HT upregulated EZH2, and the noncanonical action of EZH2 allowed the expression of TPH1-5-HT<sub>7</sub> axis leading to gemcitabine resistance and CSC population in PDAC.Prakash ChaudharyDiwakar GuragainJae-Hoon ChangJung-Ae KimMDPI AGarticlepancreatic ductal adenocarcinomagemcitabine-resistancecancer stem cellsEnhancer of zeste homolog 2tryptophan hydroxylase 15-HT<sub>7</sub>Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5305, p 5305 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	pancreatic ductal adenocarcinoma gemcitabine-resistance cancer stem cells Enhancer of zeste homolog 2 tryptophan hydroxylase 1 5-HT<sub>7</sub> Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	pancreatic ductal adenocarcinoma gemcitabine-resistance cancer stem cells Enhancer of zeste homolog 2 tryptophan hydroxylase 1 5-HT<sub>7</sub> Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Prakash Chaudhary Diwakar Guragain Jae-Hoon Chang Jung-Ae Kim TPH1 and 5-HT<sub>7</sub> Receptor Overexpression Leading to Gemcitabine-Resistance Requires Non-Canonical Permissive Action of EZH2 in Pancreatic Ductal Adenocarcinoma
description	In the present study, we investigated the regulatory mechanisms underlying overexpression of EZH2, tryptophan hydroxylase 1 (TPH1), and 5-HT<sub>7</sub>, in relation to gemcitabine resistance and CSC survival in PDAC cells. In aggressive PANC-1 and MIA PaCa-2 cells, knock-down (KD) of EZH2, TPH1, or HTR7 induced a decrease in CSCs and recovery from gemcitabine resistance, while preconditioning of less aggressive Capan-1 cells with 5-HT induced gemcitabine resistance with increased expression of EZH2, TPH1, and 5-HT<sub>7</sub>. Such effects of the gene KD and 5-HT treatment were mediated through PI3K/Akt and JAK2/STAT3 signaling pathways. EZH2 KD or GSK-126 (an EZH2 inhibitor) inhibited activities of these signaling pathways which altered nuclear level of NF-kB, Sp1, and p-STAT3, accompanied by downregulation of TPH1 and 5-HT<sub>7</sub>. Co-immunoprecipation with EZH2 and pan-methyl lysine antibodies revealed that auto-methylated EZH2 served as a scaffold for binding with methylated NF-kB and Sp1 as well as unmethylated p-STAT3. Furthermore, the inhibitor of EZH2, TPH1, or 5-HT<sub>7</sub> effectively regressed pancreatic tumor growth in a xenografted mouse tumor model. Overall, the results revealed that long-term exposure to 5-HT upregulated EZH2, and the noncanonical action of EZH2 allowed the expression of TPH1-5-HT<sub>7</sub> axis leading to gemcitabine resistance and CSC population in PDAC.
format	article
author	Prakash Chaudhary Diwakar Guragain Jae-Hoon Chang Jung-Ae Kim
author_facet	Prakash Chaudhary Diwakar Guragain Jae-Hoon Chang Jung-Ae Kim
author_sort	Prakash Chaudhary
title	TPH1 and 5-HT<sub>7</sub> Receptor Overexpression Leading to Gemcitabine-Resistance Requires Non-Canonical Permissive Action of EZH2 in Pancreatic Ductal Adenocarcinoma
title_short	TPH1 and 5-HT<sub>7</sub> Receptor Overexpression Leading to Gemcitabine-Resistance Requires Non-Canonical Permissive Action of EZH2 in Pancreatic Ductal Adenocarcinoma
title_full	TPH1 and 5-HT<sub>7</sub> Receptor Overexpression Leading to Gemcitabine-Resistance Requires Non-Canonical Permissive Action of EZH2 in Pancreatic Ductal Adenocarcinoma
title_fullStr	TPH1 and 5-HT<sub>7</sub> Receptor Overexpression Leading to Gemcitabine-Resistance Requires Non-Canonical Permissive Action of EZH2 in Pancreatic Ductal Adenocarcinoma
title_full_unstemmed	TPH1 and 5-HT<sub>7</sub> Receptor Overexpression Leading to Gemcitabine-Resistance Requires Non-Canonical Permissive Action of EZH2 in Pancreatic Ductal Adenocarcinoma
title_sort	tph1 and 5-ht<sub>7</sub> receptor overexpression leading to gemcitabine-resistance requires non-canonical permissive action of ezh2 in pancreatic ductal adenocarcinoma
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/02cdd7aa1b8f41acb4e0f8e272d84f6e
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TPH1 and 5-HT<sub>7</sub> Receptor Overexpression Leading to Gemcitabine-Resistance Requires Non-Canonical Permissive Action of EZH2 in Pancreatic Ductal Adenocarcinoma

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