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| 1.
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論文
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Nagata, Naoto ; Xu, Liang ; Kohno, Susumu ; Ushida, Yusuke ; Aoki, Yudai ; Umeda, Ryohei ; Fuke, Nobuo ; Zhuge, Fen ; Ni, Yinhua ; Nagashimada, Mayumi ; Takahashi, Chiaki ; Suganuma, Hiroyuki ; Kaneko, Shuichi ; Ota, Tsuguhito
概要:
Low-grade sustained inflammation links obesity to insulin resistance and nonalcoholic fatty liver disease (NAFLD). Howev
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er, therapeutic approaches to improve systemic energy balance and chronic inflammation in obesity are limited. Pharmacological activation of nuclear factor (erythroid-derived 2)–like 2 (Nrf2) alleviates obesity and insulin resistance in mice; however, Nrf2 inducers are not clinically available owing to safety concerns. Thus, we examined whether dietary glucoraphanin, a stable precursor of the Nrf2 inducer sulforaphane, ameliorates systemic energy balance, chronic inflammation, insulin resistance, and NAFLD in high-fat diet (HFD)–fed mice. Glucoraphanin supplementation attenuated weight gain, decreased hepatic steatosis, and improved glucose tolerance and insulin sensitivity in HFD-fed wild-type mice but not in HFD-fed Nrf2 knockout mice. Compared with vehicle-treated controls, glucoraphanin-treated HFD-fed mice had lower plasma lipopolysaccharide levels and decreased relative abundance of the gram-negative bacteria family Desulfovibrionaceae in their gut microbiomes. In HFD-fed mice, glucoraphanin increased energy expenditure and the protein expression of uncoupling protein 1 (Ucp1) in inguinal and epididymal adipose depots. Additionally, in this group, glucoraphanin attenuated hepatic lipogenic gene expression, lipid peroxidation, classically activated M1-like macrophage accumulation, and inflammatory signaling pathways. By promoting fat browning, limiting metabolic endotoxemia-related chronic inflammation, and modulating redox stress, glucoraphanin may mitigate obesity, insulin resistance, and NAFLD.
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| 2.
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論文
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Shamma, Awad ; Suzuki, Misa ; Hayashi, Naoyuki ; Kobayashi, Masahiko ; Sasaki, Nobunari ; Nishiuchi, Takumi ; Doki, Yuichiro ; Okamoto, Takahiro ; Kohno, Susumu ; Muranaka, Hayato ; Kitajima, Shunsuke ; Yamamoto, Ken-ichi ; Takahashi, Chiaki
概要:
The retinoblastoma tumor suppressor gene (RB) product has been implicated in epigenetic control of gene expression owing to its ability to physically bind to many chromatin modifiers. However, the biological and clinical significance of
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this activity was not well elucidated. To address this, we performed genetic and epigenetic analyses in an Rb-deficient mouse thyroid C cell tumor model. Here we report that the genetic interaction of Rb and ATM regulates DNMT1 protein stability and hence controls the DNA methylation status in the promoters of at least the Ink4a, Shc2, FoxO6, and Noggin genes. Furthermore, we demonstrate that inactivation of pRB promotes Tip60 (acetyltransferase)-dependent ATM activation; allows activated ATM to physically bind to DNMT1, forming a complex with Tip60 and UHRF1 (E3 ligase); and consequently accelerates DNMT1 ubiquitination driven by Tip60-dependent acetylation. Our results indicate that inactivation of the pRB pathway in coordination with aberration in the DNA damage response deregulates DNMT1 stability, leading to an abnormal DNA methylation pattern and malignant progression.
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| 3.
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論文
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Salah, Mohammed ; Nishimoto, Yuuki ; Kohno, Susumu ; Kondoh, Atsushi ; Kitajima, Shunsuke ; Muranaka, Hayato ; Nishiuchi, Takumi ; Ibrahim, Ahmed ; Yoshida, Akiyo ; Takahashi, Chiaki
概要:
Mutations in RB and PTEN are linked to castration resistance and poor prognosis in prostate cancer. Identification of ge
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nes that are regulated by these tumor suppressors in a context that recapitulates cancer progression may be beneficial for discovering novel therapeutic targets. Although various genetically engineered mice thus far provided tumor models with various pathological stages, they are not ideal for detecting dynamic changes in gene transcription. Additionally, it is difficult to achieve an effect specific to tumor progression via gain of functions of these genes. In this study, we developed an in vitro model to help identify RB- and PTEN-loss signatures during the malignant progression of prostate cancers. Trp53−/−; Rbf/f, Trp53−/−; Ptenf/f, and Trp53−/−; Rbf/f; Ptenf/f prostate epithelial cells were infected with AD-LacZ or AD-Cre. We found that deletion of Rb, Pten or both stimulated prostasphere formation and tumor development in immune-compromised mice. The GO analysis of genes affected by the deletion of Rb or Pten in Trp53−/− prostate epithelial cells identified a number of genes encoding cytokines, chemokines and extracellular matrix remodeling factors, but only few genes related to cell cycle progression. Two genes (Il-6 and Lox) were further analyzed. Blockade of Il-6 signaling and depletion of Lox significantly attenuated prostasphere formation in 3D culture, and in the case of IL-6, strongly suppressed tumor growth in vivo. These findings suggest that our in vitro model may be instrumental in identifying novel therapeutic targets of prostate cancer progression, and further underscore IL-6 and LOX as promising therapeutic targets. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.<br />Embargo Period 12 months
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| 4.
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論文
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Yoshida, Akiyo ; Kitajima, Shunsuke ; Li, Fengkai ; Cheng, Chaoyang ; Takegami, Yujiro ; Kohno, Susumu ; Wan, Yuan Song ; Hayashi, Naoyuki ; Muranaka, Hayato ; Nishimoto, Yuuki ; Nagatani, Naoko ; Nishiuchi, Takumi ; Thai, Tran C ; Suzuki, Sawako ; Nakao, Shinji ; Tanaka, Tomoaki ; Hirose, Osamu ; Barbie, David A. ; Takahashi, Chiaki
概要:
We established an in vitro cell culture system to determine novel activities of the retinoblastoma (Rb) protein during tumor progression. Rb depletion in p53-null mouse-derived soft tissue sarcoma cells induced a spherogenic
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phenotype. Cells retrieved from Rb-depleted spheres exhibited slower proliferation and less efficient BrdU incorporation, however, much higher spherogenic activity and aggressive behavior. We discovered six miRNAs, including mmu-miR-18a, -25, -29b, -140, -337, and -1839, whose expression levels correlated tightly with the Rb status and spherogenic activity. Among these, mmu-miR-140 appeared to be positively controlled by Rb and to antagonize the effect of Rb depletion on spherogenesis and tumorigenesis. Furthermore, among genes potentially targeted by mmu-miR-140, Il-6 was upregulated by Rb depletion and downregulated by mmu-mir-140 overexpression. Altogether, we demonstrate the possibility that mmu-mir-140 mediates the Rb function to downregulate Il-6 by targeting its 3'-untranslated region. Finally, we detected the same relationship among RB, hsa-miR-140 and IL-6 in a human breast cancer cell line MCF-7. Because IL-6 is a critical modulator of malignant features of cancer cells and the RB pathway is impaired in the majority of cancers, hsa-miR-140 might be a promising therapeutic tool that disrupts linkage between tumor suppressor inactivation and pro-inflammatory cytokine response.<br />Supplementary Table1 and Supplementary Table2: We offer the table data with an Excel file
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| 5.
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Adachi, Eri ; Ali, Mohamed A.E. ; Baba, Tomohisa ; Domoto, Takahiro ; Endo, Yoshio ; Enkhtuya, Radnaa ; Gunarta, I Ketut ; Han, Tae-Su ; Hayashi, Naoyuki ; Hirose, Mayumi ; Ishimura, Akihiko ; Ju, Xiaoli ; Kasada, Atsuo ; Kitajima, Shunsuke ; Kohno, Susumu ; Kushiyama, Hiroko ; Li, Zichen ; Nishimura, Tatsunori ; Ohta, Kumiko ; Sakai, Katsuya ; Sasaki, Nobunari ; Sato, Tokiharu ; Song, Yao ; Tadokoro, Yuko ; Yamada, Daisuke ; Yoshida, Akiyo ; Yoshimoto, Taisuke ; Zhao, Lu
概要:
International Symposium on Tumor Biology in Kanazawa & Symposium on Drug Discoverry in Academics 2014 [DATE]: January 23(Thu)-24(Fri),2014, [Place]:Kanazawa Excel Hotel Tpkyu, Kanazawa, Japan, [Organizers]:Kanazawa
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Association of Tumor Biologists / Cancer Research Institute, Kanazawa University
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| 6.
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その他
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Sasaki, Nobunari ; Uema, Noriyuki ; Ishikawa, Tomo-o ; Sasaki, Soichiro ; Kono, Yusuke ; Azuma, Masahiro ; Ju, Xiaoli ; Lu, Zhao ; Sato, Yumi ; Kashiba, Yui ; Yamamoto, Koji ; Lin, Yang ; Wang, Zhe ; Shimizu, Yuko ; Murata, Takayuki ; Domoto, Takahiro ; Oktyabri, Dulamsuren ; Sakai, Katsuya ; Hayashi, Naoyuki ; Kobayashi, Masahiko ; Yamakoshi, Nana ; Kobayashi, Akiko ; Tsuka, Eriko ; Yamada, Daisuke ; Sano, Takako ; Tange, Shoichiro ; Sato, Tokiharu ; Kohno, Susumu ; Muranaka, Hayato ; Hirose, Mayumi
概要:
The 3rd International Symposium on Carcinogenic Spiral & International Symposium on Tumor Biology in Kanazawa, [DATE]: January 24(Thu)-25(Fri),2013, [Place]:Kanazawa Excel Hotel Tpkyu, Kanazawa, Japan,
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[Organizers]:Infection/Inflammation-Assisted Acceleration of the Carcinogenic Spiral and its Alteration through Vector Conversion of the Host Response to Tumors / Scientific Research on Innovative Areas, a MEXT Grant-in Aid Project
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| 7.
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論文
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河野, 晋 ; Kohno, Susumu
概要:
金沢大学がん進展制御研究所<br />がん抑制遺伝子RBの不活性化は、がん悪性進展課程において、高頻度に観察される。これまでに、RB追加欠損モデルの解析を行い、RB・ｐ53複合欠損マウス甲状腺C細胞は高度な未分化性を獲得することや、ｐ53欠
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損したがん細胞では、RBの追加欠損によりがん幹細胞様集団が出現することを見出している。本研究では、がん幹細胞様集団の代謝に着目し、その動態を解析することで、PGAMががん幹細胞様集団の未分化性の維持に必要であることを明らかにした。さらに、RBによるPGAMの発現調節はヒストン脱メチル化酵素を介して行われることを明らかにした。<br />Inactivation of the tumor suppressor gene RB is frequently observed in cancer progression. We analyzed the model lacking RB additionally and found that thyroid C cells of RB ・ p53-deficient mice acquire high undifferentiated property. In addition, we also found that cancer stem cell-like populations appear due to the additional deficiency of RB in p53 deficient cancer cells. In this study, we focused on the metabolism of cancer stem cell - like population and analyzed its dynamics, revealing that PGAM is necessary for maintaining the undifferentiated state of cancer stem cell - like population. Furthermore, it was revealed that regulation of PGAM expression by RB is mediated through histone demethylase.<br />研究課題/領域番号:15K18404, 研究期間(年度):2015-04-01 - 2019-03-31
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| 8.
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論文
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河野, 晋 ; Kohno, Susumu
概要:
解糖系あるいはTCA回路において産生される代謝中間体は、様々な経路において利用される。我々は、がん悪性進展過程において高頻度に不活性化されるがん抑制遺伝子RBに着目し、解糖系酵素PGAM1がRBの支配下にあることを見出している。本研究では、
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RB不活性化により起こる代謝変化に着目し、エピジェネティクスに与えるインパクトを解析した。その結果、RBはKDM5Aを介して、胃がんにおけるグローバルなメチル化を制御し、種々の解糖系酵素がその支配下にあることを明らかにした。加えて、RB依存的な細胞分化する系において、PGAMが細胞分化を制御することが見出した。<br />The metabolic intermediates produced in the glycolytic or TCA cycle are utilized in various pathways. We focused on the tumor suppressor gene RB, which is frequently inactivated in the malignant progression of cancer, and found that the expression of glycolytic enzyme PGAM1 is regulated by RB. In this study, we focused on the metabolic changes caused by RB inactivation and analyzed the impact given by the metabolic alteration on epigenetics. As a result, RB regulates global methylation in gastric cancer via KDM5A, and it is revealed that various glycolytic enzymes are controlled by the RB-KDM5A axis. In addition, we found that PGAM contributes RB dependent cell differentiation in myogenesis of C2C12 and adipogenesis of 3T3L1.<br />研究課題/領域番号:17K14992, 研究期間(年度):2017-04-01 - 2019-03-31<br />出典：研究課題「PGAMによるエピジェネティクスリモデリングを介したがん悪性化機構の解明」課題番号17K14992（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-17K14992/17K14992seika/）を加工して作成
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