Nicotinamide N‐methyltransferase is related to MELF pattern invasion in endometrioid carcinoma

Abstract Grade 1 (G1) endometrioid carcinoma (EC) is relatively a good prognosis. However, in a minority of cases, G1 shows an aggressive histological pattern known as the microcystic, elongated, and fragmented (MELF) pattern. We previously reported that EC with high expression levels of S100A4 and...

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Autores principales:	Shinichiro Tahara, Satoshi Nojima, Kenji Ohshima, Yumiko Hori, Kazuaki Sato, Masako Kurashige, Takahiro Matsui, Daisuke Okuzaki, Eiichi Morii
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	endometrioid carcinoma invasion MELF migration NNMT Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/7dc2bba835ba4ce4b051b39fc07a59de
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spelling	oai:doaj.org-article:7dc2bba835ba4ce4b051b39fc07a59de2021-12-01T04:49:16ZNicotinamide N‐methyltransferase is related to MELF pattern invasion in endometrioid carcinoma2045-763410.1002/cam4.4359https://doaj.org/article/7dc2bba835ba4ce4b051b39fc07a59de2021-12-01T00:00:00Zhttps://doi.org/10.1002/cam4.4359https://doaj.org/toc/2045-7634Abstract Grade 1 (G1) endometrioid carcinoma (EC) is relatively a good prognosis. However, in a minority of cases, G1 shows an aggressive histological pattern known as the microcystic, elongated, and fragmented (MELF) pattern. We previously reported that EC with high expression levels of S100A4 and serum deprivation‐response protein (SDPR) was related to MELF pattern invasion. However, the molecular features of the invasive front area of the MELF pattern have not been investigated. In this study, we searched for genes preferentially expressed in the invasive front area of EC with the MELF pattern using laser microdissection and RNA sequencing, and showed that nicotinamide N‐methyltransferase (NNMT) is related to MELF pattern invasiveness. Immunohistochemical analyses confirmed high NNMT expression in the invasive front area of the MELF pattern. Moreover, NNMT promoted migration, invasion, colony formation, epithelial–mesenchymal transition (EMT), and chemoresistance using EC cell lines. We speculate that depletion of NNMT promotes histone methylation and leads to tumor suppression because NNMT consumes S‐adenosyl methionine (SAM), which is an essential methylation cofactor. NNMT knockout cells showed enhanced expression of H3K9me2. RNA sequencing using NNMT knockout cell lines suggested that methylation of H3K9 leads to repression of the transcription of various oncogenic genes. Our findings demonstrate the possibility that NNMT inhibitors, which are expected to be used for the treatment of metabolic disorders, would be effective for the treatment of aggressive EC. This is the first report of gene analyses focusing on the morphological changes associated with MELF pattern invasion of EC.Shinichiro TaharaSatoshi NojimaKenji OhshimaYumiko HoriKazuaki SatoMasako KurashigeTakahiro MatsuiDaisuke OkuzakiEiichi MoriiWileyarticleendometrioid carcinomainvasionMELFmigrationNNMTNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancer Medicine, Vol 10, Iss 23, Pp 8630-8640 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	endometrioid carcinoma invasion MELF migration NNMT Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	endometrioid carcinoma invasion MELF migration NNMT Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Shinichiro Tahara Satoshi Nojima Kenji Ohshima Yumiko Hori Kazuaki Sato Masako Kurashige Takahiro Matsui Daisuke Okuzaki Eiichi Morii Nicotinamide N‐methyltransferase is related to MELF pattern invasion in endometrioid carcinoma
description	Abstract Grade 1 (G1) endometrioid carcinoma (EC) is relatively a good prognosis. However, in a minority of cases, G1 shows an aggressive histological pattern known as the microcystic, elongated, and fragmented (MELF) pattern. We previously reported that EC with high expression levels of S100A4 and serum deprivation‐response protein (SDPR) was related to MELF pattern invasion. However, the molecular features of the invasive front area of the MELF pattern have not been investigated. In this study, we searched for genes preferentially expressed in the invasive front area of EC with the MELF pattern using laser microdissection and RNA sequencing, and showed that nicotinamide N‐methyltransferase (NNMT) is related to MELF pattern invasiveness. Immunohistochemical analyses confirmed high NNMT expression in the invasive front area of the MELF pattern. Moreover, NNMT promoted migration, invasion, colony formation, epithelial–mesenchymal transition (EMT), and chemoresistance using EC cell lines. We speculate that depletion of NNMT promotes histone methylation and leads to tumor suppression because NNMT consumes S‐adenosyl methionine (SAM), which is an essential methylation cofactor. NNMT knockout cells showed enhanced expression of H3K9me2. RNA sequencing using NNMT knockout cell lines suggested that methylation of H3K9 leads to repression of the transcription of various oncogenic genes. Our findings demonstrate the possibility that NNMT inhibitors, which are expected to be used for the treatment of metabolic disorders, would be effective for the treatment of aggressive EC. This is the first report of gene analyses focusing on the morphological changes associated with MELF pattern invasion of EC.
format	article
author	Shinichiro Tahara Satoshi Nojima Kenji Ohshima Yumiko Hori Kazuaki Sato Masako Kurashige Takahiro Matsui Daisuke Okuzaki Eiichi Morii
author_facet	Shinichiro Tahara Satoshi Nojima Kenji Ohshima Yumiko Hori Kazuaki Sato Masako Kurashige Takahiro Matsui Daisuke Okuzaki Eiichi Morii
author_sort	Shinichiro Tahara
title	Nicotinamide N‐methyltransferase is related to MELF pattern invasion in endometrioid carcinoma
title_short	Nicotinamide N‐methyltransferase is related to MELF pattern invasion in endometrioid carcinoma
title_full	Nicotinamide N‐methyltransferase is related to MELF pattern invasion in endometrioid carcinoma
title_fullStr	Nicotinamide N‐methyltransferase is related to MELF pattern invasion in endometrioid carcinoma
title_full_unstemmed	Nicotinamide N‐methyltransferase is related to MELF pattern invasion in endometrioid carcinoma
title_sort	nicotinamide n‐methyltransferase is related to melf pattern invasion in endometrioid carcinoma
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/7dc2bba835ba4ce4b051b39fc07a59de
work_keys_str_mv	AT shinichirotahara nicotinamidenmethyltransferaseisrelatedtomelfpatterninvasioninendometrioidcarcinoma AT satoshinojima nicotinamidenmethyltransferaseisrelatedtomelfpatterninvasioninendometrioidcarcinoma AT kenjiohshima nicotinamidenmethyltransferaseisrelatedtomelfpatterninvasioninendometrioidcarcinoma AT yumikohori nicotinamidenmethyltransferaseisrelatedtomelfpatterninvasioninendometrioidcarcinoma AT kazuakisato nicotinamidenmethyltransferaseisrelatedtomelfpatterninvasioninendometrioidcarcinoma AT masakokurashige nicotinamidenmethyltransferaseisrelatedtomelfpatterninvasioninendometrioidcarcinoma AT takahiromatsui nicotinamidenmethyltransferaseisrelatedtomelfpatterninvasioninendometrioidcarcinoma AT daisukeokuzaki nicotinamidenmethyltransferaseisrelatedtomelfpatterninvasioninendometrioidcarcinoma AT eiichimorii nicotinamidenmethyltransferaseisrelatedtomelfpatterninvasioninendometrioidcarcinoma
_version_	1718405732108337152

Nicotinamide N‐methyltransferase is related to MELF pattern invasion in endometrioid carcinoma

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