Identification of a histone modifier that affects pancreatic cancer progression

• Project/Area Number: 23591009
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: TATEISHI Keisuke 東京大学, 医学部附属病院, 講師 (20396948)
• Co-Investigator(Kenkyū-buntansha): KOGURE Hirofumi 東京大学, 医学部附属病院, 助教 (60568921) ; SASAKI Takashi 東京大学, 医学部附属病院, 助教 (10569106) ; YAMAMOTO Natsuyo 東京大学, 医学部附属病院, 助教 (40599578)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 膵がん / ヒストン修飾 / エピジェネテイクス / 膵癌

Research Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease where virtually all tumors harbor mutations in KRAS and other tumor suppressor genes. Though recent studies provide evidence that epigenetic changes, as well as genetic mutations, are involved in the initiation and progression of cancer, the impact of epigenetic alteration in PDAC is yet to be determined.Here we focused on the histone H3 Lys 27 (H3K27) demethylase KDM6B. KDM6B is a putative tumor suppressor and previous reports have shown that KDM6B is upregulated under oncogenic KRAS mutations and activates tumor suppressor p16/CDKN2A, thus inducing oncogene-induced senescence (OIS) in premalignant lesions. In this work, we identified a novel tumor suppressive mechanism by KDM6B, distinct from the KRAS-KDM6B-p16 mediated induction of OIS. We provide evidence that loss of KDM6B-C/EBP axis enhances tumorigenesis in PDAC cells.

Research Products

• [Journal Article] Disease-Specific Mortality Among Patients With Intraductal Papillary Mucinous Neoplasm of the Pancreas (2014)
  • Author(s): Kawakubo K, Tada M, Isayama H, Sasahira N, Nakai Y, Takahara N, Uchino R, Hamada T, Miyabayashi K, Yamamoto K, Mizuno S, Mohri D, Kogure H, Sasaki T, Yamamoto N, Hirano K, Ijichi H, Tateishi K, Koike K
  • Journal Title: Clin Gastroenterol Hepatol Volume: 12(3) (2013 Jul 25) Issue: 3 Pages: 486-91
  • DOI: 10.1016/j.cgh.2013.06.032
  • Peer Reviewed
• [Journal Article] A retrospective analysis of early CA19-9 change in salvage chemotherapy for refractory pancreatic cancer (2013)
  • Author(s): Nakai Y, Isayama H, Sasaki T, Takahara N, Hamada T, Uchino R, Mizuno S, Miyabayashi K, Yamamoto K, Mohri D, Kogure H, Yamamoto N, Hirano K, Ijichi H, Tateishi K, Tada M, Koike K
  • Journal Title: Cancer Chemother Pharmacol
• [Journal Article] A retrospective study of S-1 and oxaliplatin combination chemotherapy in patients with refractory pancreatic cancer (2013)
  • Author(s): Takahara N, Isayama H, Nakai Y, Sasaki T, Hamada T, Uchino R, Mizuno S, Miyabayashi K, Kogure H, Yamamoto N, Sasahira N, Hirano K, Ijichi H, Tateishi K, Tada M, Koike K
  • Journal Title: Cancer Chemother Pharmacol Volume: 72(5) Pages: 985-90
• [Journal Article] Diabetes is a useful diagnostic clue to improve the prognosis of pancreatic cancer (2013)
  • Author(s): Mizuno S, Nakai Y, Isayama H, Takahara N, Miyabayashi K, Yamamoto K, Kawakubo K, Mohri D, Kogure H, Sasaki T, Yamamoto N, Sasahira N, Hirano K, Tsujino T, Ijichi H, Tateishi K, Tada M, Koike K
  • Journal Title: Pancreatology Volume: 13(3) Pages: 285-9
• [Journal Article] Histone demethylase KDM4C regulates sphere formation by mediating the cross talk between Wnt and Notch pathways in colonic cancer cells. (2013)
  • Author(s): Yamamoto S, Tateishi K, Kudo Y, Yamamoto K, Isagawa T, Nagae G, Nakatsuka T, Asaoka Y, Ijichi H, Hirata Y, Otsuka M, Ikenoue T, Aburatani H, Omata M, Koike K.
  • Journal Title: Carcinogenesis Volume: 10 Issue: 10 Pages: 2380-8
  • DOI: 10.1093/carcin/bgt174
  • Peer Reviewed
• [Journal Article] A multicenter phase II trial of gemcitabine and candesartan combination therapy in patients with advanced pancreatic cancer: GECA2 (2013)
  • Author(s): Nakai Y, Isayama H, Ijichi H, Sasaki T, Takahara N, Ito Y, Matsubara S, Uchino R, Yagioka H, Arizumi T, Hamada T, Miyabayashi K, Mizuno S, Yamamoto K, Kogure H, Yamamoto N, Hirano K, Sasahira N, Tateishi K, Tada M, Koike K
  • Journal Title: Invest New Drugs Volume: 31(5) Pages: 1294-9
• [Journal Article] Erlotinib prolongs survival in pancreatic cancer by blocking gemcitabine-induced MAPK signals. (2013)
  • Author(s): Miyabayashi K, Ijichi H, Mohri D, Tada M, Yamamoto K, Asaoka Y, Ikenoue T, Tateishi K, Nakai Y, Isayama H, Morishita Y, Omata M, Moses HL, Koike K.
  • Journal Title: Cancer Res Volume: 73 Issue: 7 Pages: 2221-34
  • DOI: 10.1158/0008-5472.can-12-1453
  • Peer Reviewed
• [Journal Article] Risk for mortality from causes other than pancreatic cancer in patients with intraductal papillary mucinous neoplasm of the pancreas (2013)
  • Author(s): Kawakubo K, Tada M, Isayama H, Sasahira N, Nakai Y, Takahara N, Miyabayashi K, Yamamoto K, Mizuno S, Mohri D, Kogure H, Sasaki T, Yamamoto N, Tateishi R, Hirano K, Ijichi H, Tateishi K, Koike K
  • Journal Title: Pancreas Volume: 42(4) Issue: 4 Pages: 687-91
  • DOI: 10.1097/mpa.0b013e318270ea97
  • Peer Reviewed
• [Journal Article] Clinical outcomes ofchemotherapy for diabetic and nondiabetic patients with pancreatic cancer: better prognosis with statin use in diabetic patients (2013)
  • Author(s): Nakai Y, Isayama H, Sasaki T, Mizuno S, Sasahira N, Kogure H, Kawakubo K, Yamamoto N, Hirano K, Ijichi H, Tateishi K, Tada M, Koike K
  • Journal Title: Pancreas Volume: 42(2) Pages: 202-8
• [Journal Article] Risk factors and early signs of pancreatic cancer in diabetes: screening strategy based on diabetes onset age (2013)
  • Author(s): Mizuno S, Nakai Y, Isayama H, Yanai A, Takahara N, Miyabayashi K, Yamamoto K, Kawakubo K, Mohri D, Kogure H, Sasaki T, Yamamoto N, Sasahira N, Hirano K, Tsujino T, Ijichi H, Tateishi K, Akanuma M, Tada M, Koike K
  • Journal Title: J Gastroenterol Volume: 48(2) Pages: 238-46
  • NAID: 10031156309
• [Journal Article] rlotinib prolongs survival in pancreatic cancer by blocking gemcitabine-induced MAPK signals. (2013)
  • Author(s): Miyabayashi K, Ijichi H, Mohri D, Tada M, Yamamoto K, Asaoka Y, Ikenoue T, Tateishi K, Nakai Y, Isayama H, Morishita Y, Omata M, Moses HL, Koike K.
  • Journal Title: Cancer Res Volume: 73 Pages: 2221-34
  • Peer Reviewed
• [Journal Article] Phase I trial of gemcitabine and candesartan combination therapy in normotensive patients with advanced pancreatic cancer: GECA1 (2012)
  • Author(s): Nakai Y, Isayama H, Ijichi H, Sasaki T, Kogure H, Yagioka H, Miyabayashi K, Mizuno S, Yamamoto K, Mouri D, Kawakubo K, Yamamoto N, Hirano K, Sasahira N, Tateishi K, Tada M, Koike K
  • Journal Title: Cancer Sci Volume: 103(8) Pages: 1489-92
• [Journal Article] Loss of 5-hydroxymethylcytosine is accompanied with malignant cellular transformation (2012)
  • Author(s): Kudo Y, Tateishi K, Yamamoto K, Yamamoto S, Asaoka Y, Ijichi H, Nagae G, Yoshida H, Aburatani H, Koike K
  • Journal Title: Cancer Sci Volume: 103(4) Pages: 670-6
• [Journal Article] Different subtypes of intraductal papillary mucinous neoplasm in the pancreas have distinct pathways to pancreatic cancer progression (2012)
  • Author(s): Mohri D, Asaoka Y, Ijichi H, Miyabayashi K, Kudo Y, Seto M, Ohta M, Tada M, Tanaka Y, Ikenoue T, Tateishi K, Isayama H, Kanai F, Fukushima N, Tada M, Kawabe T, Omata M, Koike K
  • Journal Title: J Gastroenterol Volume: 47(2) Pages: 203-13
  • NAID: 10030296319
• [Journal Article] Loss of 5-hydroxymethylcytosine is accompanied with malignant cellular transformation. (2012)
  • Author(s): Kudo Y, Tateishi K, Yamamoto K, Yamamoto S, Asaoka Y, Ijichi H, Nagae G, Yoshida H, Aburatani H, Koike K.
  • Journal Title: Cancer Sci Volume: 103 Pages: 670-6
  • Peer Reviewed
• [Journal Article] Different subtypes of intraductal papillary mucinous neoplasm in the pancreas have distinct pathways to pancreatic cancer progression. (2012)
  • Author(s): Mohri D, Asaoka Y, Ijichi H, Miyabayashi K, Kudo Y, Seto M, Ohta M, Tada M, Tanaka Y, Ikenoue T, Tateishi K, Isayama H, Kanai F, Fukushima N, Tada M, Kawabe T, Omata M, Koike K.
  • Journal Title: J Gastroenterol Volume: 47 Pages: 203-13
  • NAID: 10030296319
  • Peer Reviewed
• [Journal Article] Inhibiting Cxcr2 disrupts tumor-stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma (2011)
  • Author(s): Ijichi H, Chytil A, Gorska AE, Aakre ME, Bierie B, Tada M, Mohri D, Miyabayashi K, Asaoka Y, Maeda S, Ikenoue T, Tateishi K, Wright CV, Koike K, Omata M, Moses HL
  • Journal Title: J Clin Invest Volume: 121(10) Pages: 4106-17
• [Journal Article] Altered composition of fatty acids exacerbates hepatotumorigenesis during activation of the phosphatidylinositol 3-kinase pathway (2011)
  • Author(s): Kudo Y, Tanaka Y, Tateishi K, Yamamoto K, Yamamoto S, Mohri D, Isomura Y, Seto M, Nakagawa H, Asaoka Y, Tada M, Ohta M, Ijichi H, Hirata Y, Otsuka M, Ikenoue T, Maeda S, Shiina S, Yoshida H, Nakajima O, Kanai F, Omata M, Koike K
  • Journal Title: J Hepatol Volume: 55(6) Pages: 1400-8
• [Journal Article] Incidence of extrapancreatic malignancies in patients with intraductal papillary mucinous neoplasms of the pancreas (2011)
  • Author(s): Kawakubo K, Tada M, Isayama H, Sasahira N, Nakai Y, Yamamoto K, Kogure H, Sasaki T, Hirano K, Ijichi H, Tateishi K, Yoshida H, Koike K
  • Journal Title: Gut Volume: 60(9) Pages: 1249-53
• [Journal Article] Recent progress and limitations of chemotherapy for pancreatic and biliary tract cancers (2011)
  • Author(s): Tada M, Nakai Y, Sasaki T, Hamada T, Nagano R, Mohri D, Miyabayashi K, Yamamoto K, Kogure H, Kawakubo K, Ito Y, Yamamoto N, Sasahira N, Hirano K, Ijichi H, Tateishi K, Isayama H, Omata M, Koike K
  • Journal Title: World J Clin Oncol Volume: 2(3) Pages: 158-163
• [Journal Article] Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer (2011)
  • Author(s): Hayakawa Y, Hirata Y, Nakagawa H, Sakamoto K, Hikiba Y, Kinoshita H, Nakata W, Takahashi R, Tateishi K, Tada M, Akanuma M, Yoshida H, Takeda K, Ichijo H, Omata M, Maeda S, Koike K
  • Journal Title: Proc Natl Acad Sci U S A Volume: 108(2) Pages: 780-5
• [Journal Article] Reduced expression of RAS protein activator like-1 in gastric cancer (2011)
  • Author(s): Seto M, Ohta M, Ikenoue T, Sugimoto T, Asaoka Y, Tada M, Mohri D, Kudo Y, Ijichi H, Tateishi K, Otsuka M, Hirata Y, Maeda S, Koike K, Omata M
  • Journal Title: Int J Cancer Volume: 128(6) Pages: 1293-302
• [Presentation] ヒストン修飾酵素JHDM3CはWnt-Notch シグナルのメデイエーターとして大腸腫瘍形成能を制御する (2013)
  • Author(s): 山本信三、立石敬介、工藤洋太郎、山本恵介、砂河孝行、永江玄太、中塚拓馬、浅岡良成、伊地知秀明、小俣政男、油谷浩幸、小池和彦
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-04
• [Presentation] KDM4C regulates sphere formation by mediating the crosstalk between Wnt and Notch pathways in colonic cancer cells (2013)
  • Author(s): 山本信三、立石敬介、工藤洋太郎、山本恵介、砂河孝行、永江玄太、油谷浩幸、小池和彦
  • Organizer: Cell symposia
  • Place of Presentation: Spain
• [Presentation] Contribution of TET1 to malignant characteristics in digestive cancer cells (2013)
  • Author(s): 工藤洋太郎、立石敬介、池上恒雄、山本恵介、永江玄太、米澤理人、関元昭、白井、油谷浩幸、小池和彦
  • Organizer: Cell symposia
  • Place of Presentation: Spain
• [Presentation] Contribution of TET1 to malignant characteristics in digestive cancer cells. (2013)
  • Author(s): Y. Kudo, K. Tateishi, T. Ikenoue, K. Yamamoto, G. Nagae, M. Yonezawa, M. Seki, K. Shirai, H. Aburatani, K. Koike
  • Organizer: Cell symposia “Cancer Epigenomics”
  • Place of Presentation: Spain, Sitges
• [Presentation] KDM4C regulates sphere formation by mediating the crosstalk between Wnt and Notch pathways in colonic cancer cells. (2013)
  • Author(s): S. Yamamoto, K. Tateishi, Y. Kudo, K. Yamamoto, T. Isagawa, G. Nagae, H. Aburatani, K. Koike
  • Organizer: Cell symposia “Cancer Epigenomics”
  • Place of Presentation: Spain, Sitges
• [Presentation] 膵発癌モデルマウスを用いたゲムシタビンとエルロチニブの効果・メカニズムの検討 膵癌:基礎研究 (2012)
  • Author(s): 宮林弘至,伊地知秀明,毛利大,多田素久,山本恵介,浅岡良成,池上恒雄,立石敬介,中井陽介,伊佐山浩通,多田稔,小池和彦
  • Organizer: 第43回日本膵臓学会大会
  • Place of Presentation: 山形
  • Year and Date: 2012-06-29
• [Presentation] 悪性形質転換におけるヒドロキシメチル化シトシンの低下 (2012)
  • Author(s): 工藤洋太郎, 立石敬介, 山本恵介, 山本信三, 浅岡良成, 伊地知秀明, 永江玄太, 油谷浩幸, 小池和彦
  • Organizer: 第6回 日本エピジェネティクス研究会年会
  • Place of Presentation: 東京 (ポスター討論)
  • Year and Date: 2012-05-15
• [Presentation] Pancreatic ductal adenocarcinoma can arise from Nestin- positive progenitor cells in the adult pancreas (2012)
  • Author(s): 伊地知秀明、宮林功至、多田素久、浅岡良成、池上恒雄、立石敬介、小俣政男、小池和彦
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] Loss of 5-hydroxymethylcytosine is accompanied with malignant cellular transformation (2012)
  • Author(s): 工藤洋太郎、立石敬介、山本恵介、山本信三、浅岡良成、伊地知秀明、永江玄太、油谷浩幸、小池和彦
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] 悪性形質転換におけるヒドロキシメチル化シトシンの低下 (2012)
  • Author(s): 工藤洋太郎、立石敬介、小池和彦
  • Organizer: 日本エピジェネテクス研究会年会
  • Place of Presentation: 東京
• [Presentation] Hippoシグナル異常を伴う肝細胞癌における受容体型チロシンキナーゼに関する検討 (2011)
  • Author(s): 浅岡良成,池上恒雄,多田素久,建石良介,伊地知秀明,立石敬介,金井文彦,椎名秀一朗,吉田晴彦,小俣政男,小池和彦
  • Organizer: 第19回JDDW/ 第15回日本肝臓学会大会
  • Place of Presentation: 福岡
  • Year and Date: 2011-10-20
• [Presentation] The exploration of novel strategy for treatment of pancreactic ductal adenocarcinoma using genetically engineered mouse Novel target molecule (2011)
  • Author(s): 多田素久, 伊地知秀明, 宮林弘至, 浅岡良成,毛利大, 池上恒雄, 立石敬介, 石原武, 金井文彦, 今関文夫, Moses Harold L., 小俣政男, 横須賀收
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-04
• [Presentation] 膵癌微小環境におけるCXC ケモカイン/CXCR2Axis 阻害の重要性 Intercellular Interaction and Tumor Microenvironment (2011)
  • Author(s): 伊地知秀明,多田素久,宮林弘至,浅岡良成,立石敬介,池上恒雄,小俣政男,小池和彦
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-03
• [Presentation] 肝細胞癌におけるHippo シグナルの異常に関する検討 肝発癌研究の新展開 (2011)
  • Author(s): 浅岡良成,池上恒雄,多田素久,後藤絵理子,建石良介,伊地知秀明,立石敬介,金井文彦,椎名秀一朗,吉田晴彦,小俣政男,小池和彦
  • Organizer: 第47回日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 2011-06-03
• [Presentation] 大腸癌におけるH3K9 脱メチル化酵素KDM4C の発現異常とその意義の検討 (2011)
  • Author(s): 山本信三,立石敬介,工藤洋太郎,山本恵介,浅岡良成,伊地知秀明,砂河孝行,油谷浩幸,小池和彦
  • Organizer: 第5回日本エピジェネティクス研究会
  • Place of Presentation: 熊本
  • Year and Date: 2011-05-19
• [Presentation] ヒストン脱メチル化酵素JMJD3の発現低下は膵癌の進展を促進する エピジェネティクスと消化器癌 (2011)
  • Author(s): 山本恵介,立石敬介,宮林弘至, 山本信三, 工藤洋太郎,浅岡良成,伊地知秀明,小俣政男,小池和彦
  • Organizer: 第19回JDDW
  • Place of Presentation: 福岡
• [Presentation] JHDM3C regulates sphere formation by mediating the crosstalk between Wnt and Notch pathways
  • Author(s): Shinzo Yamamoto, Keisuke Tateishi, Yotaro Kudo, Keisuke Yamamoto, Takayuki Isagawa, Genta Nagae, Takuma Nakatsuka, Yoshinari Asaoka, Hideaki Ijichi, Masao Omata, Hiroyuki Aburatani, and Kazuhiko Koike
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: ﾊﾟｼﾌｨｺ横浜
• [Book] 良性胆道腫瘍 (2012)
  • Author(s): 立石敬介
  • Total Pages: 2
  • Publisher: 西村書店