Faculty Profiles - ENOMOTO, Atsushi

Papers - ENOMOTO, Atsushi

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The role of CD109 in PDGFB-induced glioma mouse model for sensitivity to Temozolomide

Shiraki Yukihiro, Mii Shinji, Asai Naoya, Enomoto Atsushi, Momota Hiroyuki, Natsume Atsushi, Wakabayashi Toshihiko, Takahashi Masahide

CANCER SCIENCE Vol. 109 page： 1130 - 1130 2018.1

ASC amino acid transporter 2, defined by enzyme-mediated activation of radical sources, enhances malignancy of GD2-positive small-cell lung cancer. Reviewed International journal

Nobutoshi Esaki, Yuki Ohkawa, Noboru Hashimoto, Yuhsuke Tsuda, Yuhsuke Ohmi, Robiul H Bhuiyan, Norihiro Kotani, Koichi Honke, Atsushi Enomoto, Masahide Takahashi, Keiko Furukawa, Koichi Furukawa

Cancer science Vol. 109 ( 1 ) page： 141 - 153 2018.1

Language：English Publishing type：Research paper (scientific journal)

Ganglioside GD2 is specifically expressed in small-cell lung cancer (SCLC) cells, leading to enhancement of malignant phenotypes, such as cell proliferation and migration. However, how GD2 promotes malignant phenotypes in SCLC cells is not well known. In this study, to reveal the mechanisms by which GD2 increases malignant phenotypes in SCLC cells, we used enzyme-mediated activation of radical sources combined with mass spectrometry in GD2+ SCLC cells. Consequently, we identified ASC amino acid transporter 2 (ASCT2), a major glutamine transporter, which coordinately works with GD2. We showed that ASCT2 was highly expressed in glycolipid-enriched microdomain/rafts in GD2+ SCLC cells, and colocalized with GD2 in both proximity ligation assay and immunocytostaining, and bound with GD2 in immunoprecipitation/TLC immunostaining. Malignant phenotypes of GD2+ SCLC cells were enhanced by glutamine uptake, and were suppressed by L-γ-glutamyl-p-nitroanilide, a specific inhibitor of ASCT2, through reduced phosphorylation of p70 S6K1 and S6. These results suggested that ASCT2 enhances glutamine uptake in glycolipid-enriched microdomain/rafts in GD2+ SCLC cells, leading to the enhancement of cell proliferation and migration through increased phosphorylation of the mTOR complex 1 signaling axis.

DOI： 10.1111/cas.13448

Web of Science

PubMed

Aberrant super-enhancers associated with downregulation of RET finger protein overcomes chemoresistance in glioblastoma

Hirano, M; Ranjit, M; Yamamichi, A; Aoki, K; Ohka, F; Kato, T; Enomoto, A; Takahashi, M; Wakabayashi, T; Natsume, A

CANCER SCIENCE Vol. 109 page： 461 - 461 2018.1

Ganglioside GD2 coordinately works with ASCT2, which enhances malignant phenotypes in small cell lung cancer

Esaki, N; Ohkawa, Y; Hashimoto, N; Tuna, Y; Ohmi, Y; Bhuiya, R; Kotani, N; Honk, C; Enomoto, A; Takahashi, M; Furukawa, K; Furukawa, K

CANCER SCIENCE Vol. 109 page： 94 - 94 2018.1

Mechanisms for the control of amino acid signaling and drug resistance in cancer stem cells

Enomoto, A; Takahashi, M

CANCER SCIENCE Vol. 109 page： 813 - 813 2018.1

Aberrant super-enhancers associated with downregulation of RET finger protein overcomes chemoresistance in glioblastoma

Hirano Masaki, Ranjit Melissa, Yamamichi Akane, Aoki Kosuke, Ohka Fumiharu, Kato Takuya, Enomoto Atsushi, Takahashi Masahide, Wakabayashi Toshihiko, Natsume Atsushi

CANCER SCIENCE Vol. 109 page： 461-461 2018.1

Cullin-associated NEDD8-dissociated protein 1, a novel interactor of rabphilin-3A, deubiquitylates rabphilin-3A and regulates arginine vasopressin secretion in PC12 cells Reviewed

Kohtaro Nakashima, Seiji Takeuchi, Shintaro Iwama, Atsushi Kiyota, Yoshinori Yasuda, Naoko Iwata, Atsushi Enomoto, Hiroshi Arima, Yoshihisa Sugimura

Endocrine Journal Vol. 65 ( 3 ) page： 325 - 334 2018

Language：English Publishing type：Research paper (scientific journal) Publisher：Japan Endocrine Society

The molecular mechanism involved in the exocytosis of arginine vasopressin (AVP) is not fully known. Rabphilin-3A has been suggested as a novel autoantigen in infundibulo-neurohypophysitis (LINH), which leads to central diabetes insipidus through insufficient secretion of AVP. However, the role of rabphilin-3A in the pathogenesis of LINH remains unclear. Thus, the aim of the present study was to identify proteins binding rabphilin-3A in the posterior pituitary. Using glutathione S-transferase (GST)-pulldown assays and proteomic analyses, cullin-associated NEDD8-dissociated protein 1 (CAND1) was identified as a rabphilin-3A-binding protein in the posterior pituitary. Co-immunoprecipitation assays indicated that CAND1 interacted endogenously with rabphilin-3A. In addition, immunohistochemistry experiments showed that CAND1 immunoreactivity was detected mainly in the posterior pituitary, intermediate lobe, and the supraoptic nucleus in the hypothalamus, and less in the anterior lobe, partially co-localizing with rabphilin-3A. Overexpression of CAND1 resulted in deubiquitylation of rabphilin-3A in PC12 cells. Moreover, overexpression of CAND1 in PC12 cells co-transfected with AVP enhanced both basal and KCl-stimulated AVP secretion. The findings indicate that CAND1 inhibits the ubiquitylation of rabphilin-3A and positively regulates AVP secretion. These data shed light on a novel potential mechanism involving rabphilin-3A in AVP secretion, and suggest a new role of CAND1 as a regulator of hormone or neurotransmitter secretion.

DOI： 10.1507/endocrj.EJ17-0399

Web of Science

Scopus

PubMed

Significance of perivascular tumour cells defined by CD109 expression in progression of glioma Reviewed

Yukihiro Shiraki, Shinji Mii, Atsushi Enomoto, Hiroyuki Momota, Yi-Peng Han, Takuya Kato, Kaori Ushida, Akira Kato, Naoya Asai, Yoshiki Murakumo, Kosuke Aoki, Hiromichi Suzuki, Fumiharu Ohka, Toshihiko Wakabayashi, Tomoki Todo, Seishi Ogawa, Atsushi Natsume, Masahide Takahashi

JOURNAL OF PATHOLOGY Vol. 243 ( 4 ) page： 468 - 480 2017.12

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

In the progression of glioma, tumour cells often exploit the perivascular microenvironment to promote their survival and resistance to conventional therapies. Some of these cells are considered to be brain tumour stem cells (BTSCs); however, the molecular nature of perivascular tumour cells has not been specifically clarified because of the complexity of glioma. Here, we identified CD109, a glycosylphosphatidylinositol-anchored protein and regulator of multiple signalling pathways, as a critical regulator of the progression of lower-grade glioma (World Health Organization grade II/III) by clinicopathological and whole-genome sequencing analysis of tissues from human glioma. The importance of CD109-positive perivascular tumour cells was confirmed not only in human lower-grade glioma tissues but also in a mouse model that recapitulated human glioma. Intriguingly, BTSCs isolated from mouse glioma expressed high levels of CD109. CD109-positive BTSCs exerted a proliferative effect on differentiated glioma cells treated with temozolomide. These data reveal the significance of tumour cells that populate perivascular regions during glioma progression, and indicate that CD109 is a potential therapeutic target for the disease. Copyright (C) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

DOI： 10.1002/path.4981

Web of Science

PubMed

ABERRANT SUPER-ENHANCERS ASSOCIATED WITH DOWNREGULATION OF RET FINGER PROTEIN OVERCOMES CHEMORESISTANCE IN GLIOBLASTOMA

Masaki Hirano, Melissa Ranjit, Akane Yamamichi, Kosuke Aoki, Fumiharu Ohka, Takuya Kato, Atsushi Enomoto, Masahide Takahashi, Toshihiko Wakabayashi, Atsushi Natsume

NEURO-ONCOLOGY Vol. 19 page： 103 - 103 2017.11

Correlation between SPARC expression and efficacy of nab-paclitaxel for advanced gastric cancer refractory to fluoropyrimidine: An exploratory analysis of a phase II trial, CCOG1303

Kobayashi, D; Enomoto, A; Mochizuki, Y; Matsui, T; Nakayama, H; Kawase, Y; Ishigure, K; Shikano, T; Torii, K; Kodera, Y

ANNALS OF ONCOLOGY Vol. 28 2017.9

脳腫瘍マウスモデルにおけるテモゾロミド感受性に対するCD109の機能解析

白木之浩, 三井伸二, 浅井直也, 榎本篤, 百田洋之, 夏目敦至, 若林俊彦, 高橋雅英

日本癌学会総会記事 Vol. 76回 page： P - 3324 2017.9

Daple Coordinates Planar Polarized Microtubule Dynamics in Ependymal Cells and Contributes to Hydrocephalus Reviewed

Maki Takagishi, Masato Sawada, Shinya Ohata, Naoya Asai, Atsushi Enomoto, Kunihiko Takahashi, Liang Weng, Kaori Ushida, Hosne Ara, Shigeyuki Matsui, Kozo Kaibuchi, Kazunobu Sawamoto, Masahide Takahashi

CELL REPORTS Vol. 20 ( 4 ) page： 960 - 972 2017.7

Language：English Publishing type：Research paper (scientific journal) Publisher：CELL PRESS

Motile cilia in ependymal cells, which line the cerebral ventricles, exhibit a coordinated beating motion that drives directional cerebrospinal fluid (CSF) flow and guides neuroblast migration. At the apical cortex of these multi-ciliated cells, asymmetric localization of planar cell polarity (PCP) proteins is required for the planar polarization of microtubule dynamics, which coordinates cilia orientation. Daple is a disheveledassociating protein that controls the non-canonical Wnt signaling pathway and cell motility. Here, we show that Daple-deficient mice present hydrocephalus and their ependymal cilia lack coordinated orientation. Daple regulates microtubule dynamics at the anterior side of ependymal cells, which in turn orients the cilial basal bodies required for the directional cerebrospinal fluid flow. These results demonstrate an important role for Daple in planar polarity in motile cilia and provide a framework for understanding the mechanisms and functions of planar polarization in the ependymal cells.

DOI： 10.1016/j.celrep.2017.06.089

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PubMed

Corrigendum: Girdin maintains the stemness of glioblastoma stem cells (Oncogene (2012) 31 (2715-2724) DOI: 10.1038/onc.2011.466) Reviewed

A. Natsume, T. Kato, S. Kinjo, A. Enomoto, H. Toda, S. Shimato, F. Ohka, K. Motomura, Y. Kondo, T. Miyata, M. Takahashi, T. Wakabayashi

Oncogene Vol. 31 ( 22 ) page： 2715 - 2724 2017.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Nature Publishing Group

Glioblastomas (GBMs) are the most common and aggressive type of brain tumor. GBMs usually show hyperactivation of the PI3K-Akt pathway, a pro-tumorigenic signaling cascade that contributes to pathogenesis. Girdin, an actin-binding protein identified as a novel substrate of Akt, regulates the sprouting of axons and the migration of neural progenitor cells during early postnatal-stage neurogenesis in the hippocampus. Here, we show that Girdin is highly expressed in human glioblastoma (GBM). Stable Girdin knockdown in isolated GBM stem cells resulted in decreased expression of stem cell markers, including CD133, induced multilineage neural differentiation, and inhibited in vitro cell motility, ex vivo invasion, sphere-forming capacity and in vivo tumor formation. Furthermore, exogenous expression of the Akt-binding domain of Girdin, which competitively inhibits its Akt-mediated phosphorylation, diminished the expression of stem cell markers, SOX2 and nestin, and migration on the brain slice and induced the expression of neural differentiation markers glial fibrillary acidic protein/ΒIII Tubulin. Our results reveal that Girdin is required for GBM-initiating stem cells to sustain the stemness and invasive properties. © 2012 Macmillan Publishers Limited All rights reserved.

DOI： 10.1038/onc.2011.466

Scopus

Tyrosine Phosphorylation of an Actin-Binding Protein Girdin Specifically Marks Tuft Cells in Human and Mouse Gut Reviewed

Daisuke Kuga, Kaori Ushida, Shinji Mii, Atsushi Enomoto, Naoya Asai, Masato Nagino, Masahide Takahashi, Masato Asai

JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY Vol. 65 ( 6 ) page： 347 - 366 2017.6

Language：English Publishing type：Research paper (scientific journal) Publisher：SAGE PUBLICATIONS LTD

Tuft cells (TCs) are minor components of gastrointestinal epithelia, characterized by apical tufts and spool-shaped somas. The lack of reliable TC-markers has hindered the elucidation of its role. We developed site-specific and phosphorylation-status-specific antibodies against Girdin at tyrosine-1798 (pY1798) and found pY1798 immunostaining of mouse jejunum clearly depicted epithelial cells closely resembling TCs. This study aimed to validate pY1798 as a TC-marker. Double-fluorescence staining of intestines was performed with pY1798 and known TC-markers, for example, hematopoietic-prostaglandin-D-synthase (HPGDS), or doublecortin-like kinase 1 (DCLK1). Odds ratios (ORs) were calculated from cell counts to determine whether two markers were attracting (OR<1) or repelling (OR>1). In consequence, pY1798 signals strongly attracted those of known TC-markers. ORs for HPGDS in mouse stomach, small intestine, and colon were 0 for all, and 0.08 for DCLK1 in human small intestine. pY1798-positive cells in jejunum were distinct from other minor epithelial cells, including goblet, Paneth, and neuroendocrine cells. Thus, pY1798 was validated as a TC-marker. Interestingly, apoptosis inducers significantly increased relative TC frequencies despite the absence of proliferation at baseline. In conclusion, pY1798 is a novel TC-marker. Selective tyrosine phosphorylation and possible resistance to apoptosis inducers implied the activation of certain kinase(s) in TCs, which may become a clue to elucidate the enigmatic roles of TCs.

DOI： 10.1369/0022155417702586

Web of Science

PubMed

Girdin maintains the stemness of glioblastoma stem cells (vol 31, pg 2715, 2012) Reviewed

A. Natsume, T. Kato, S. Kinjo, A. Enomoto, H. Toda, S. Shimato, F. Ohka, K. Motomura, Y. Kondo, T. Miyata, M. Takahashi, T. Wakabayashi

ONCOGENE Vol. 36 ( 26 ) page： 3796 - 3796 2017.6

Significance of low mTORC1 activity in defining the characteristics of brain tumor stem cells Reviewed

Yi-Peng Han, Atsushi Enomoto, Yukihiro Shiraki, Shen-Qi Wang, Xiaoze Wang, Shinya Toyokuni, Naoya Asai, Kaori Ushida, Hosne Ara, Fumiharu Ohka, Toshihiko Wakabayashi, Jie Ma, Atsushi Natsume, Masahide Takahashi

NEURO-ONCOLOGY Vol. 19 ( 5 ) page： 636 - 647 2017.5

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS INC

The significance of mammalian target of rapamycin complex 1 (mTORC1) activity in the maintenance of cancer stem cells (CSCs) remains controversial. Previous findings showed that mTORC1 activation depleted the population of leukemia stem cells in leukemia, while maintaining the stemness in pancreatic CSCs. The purpose of this study was to examine the currently unknown role and significance of mTORC1 activity in brain tumor stem cells (BTSCs).
Basal mTORC1 activity and its kinetics were investigated in BTSC clones isolated from patients with glioblastoma and their differentiated progenies (DIFFs). The effects of nutrient deprivation and the mTORC1 inhibitors on cell proliferation were compared between the BTSCs and DIFFs. Tissue sections from patients with brain gliomas were examined for expression of BTSC markers and mTORC1 activity by immunohistochemistry.
BTSCs presented lower basal mTORC1 activity under each culture condition tested and a more rapid decline of mTORC1 activity after nutrient deprivation than observed in DIFFs. The self-renewal capacity of BTSCs was unaffected by mTORC1 inhibition, whereas it effectively suppressed DIFF proliferation. In agreement, immunohistochemical staining of glioma tissues revealed low mTORC1 activity in tumor cells positive for BTSC markers. In in vitro culture, BTSCs exhibited resistance to the antitumor agent temozolomide.
Our findings indicated the importance of low mTORC1 activity in maintaining the undifferentiated state of BTSCs, implicating the relevance of manipulating mTORC1 activity when developing future strategies that target BTSCs.

DOI： 10.1093/neuonc/now237

Web of Science

PubMed

Meflin/Islrは心臓線維化における筋線維芽細胞起源のマーカーである

原昭壽, 榎本篤, 室原豊明, 高橋雅英

日本病理学会会誌 Vol. 106 ( 1 ) page： 317 - 317 2017.3

癌性リンパ管症を呈した乳腺神経内分泌腫瘍(Neuroendocrine tumor of the breast showing carcinomatous lymphangiosis)

川崎朋範, 中井登紀子, 市原周, 長谷川正規, 岩越朱里, 榎本篤, 佐藤朋子, 浅井昌美, 西川恵理, 大林千穂

日本病理学会会誌 Vol. 106 ( 1 ) page： 335 - 335 2017.3

慢性皮膚炎症を伴うCD109ノックアウトマウスにおいて皮膚腫瘍形成は抑制される(Suppression of skin tumorigenesis in CD109-deficient mice with chronic skin inflammation)

三井伸二, 砂川真輝, 榎本篤, 村雲芳樹, 梛野正人, 高橋雅英

日本病理学会会誌 Vol. 106 ( 1 ) page： 361 - 361 2017.3

ヒトgliiomaにおけるCD109の発現(Significance of Perivascular Tumor Cells Defined by CD109 Expression)

白木之浩, 三井伸二, 榎本篤, 高橋雅英

日本病理学会会誌 Vol. 106 ( 1 ) page： 395 - 395 2017.3

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Papers - ENOMOTO, Atsushi