Identification of a novel tumor suppressive function of HIPK2 through RNA prosessing

• Project/Area Number: 24590943
• 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 Tokushima
• Principal Investigator: MASUDA Kiyoshi 徳島大学, ヘルスバイオサイエンス研究部, 講師 (00457318)
• Co-Investigator(Kenkyū-buntansha): KUWANO Yuki 徳島大学, 大学院ヘルスバイオサイエンス研究部, 助教 (00563454)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: RNAプロセシング / 選択的スプライシング / HIPK2

Outline of Final Research Achievements

We found that SRSF3 knockdown produced a novel variant of homeodomain-interacting protein kinase- 2 (HIPK2), HIPK2-Δe8, through alternative splicing and induced G1 arrest and apoptosis in HCT116 cells. Overexpression of HIPK2-Δe8 modulated the expression of genes encoding cell cycle and apoptosis regulators. Moreover, proteomic analysis of HIPK2-associated proteins using liquid chromatography-tandem mass spectrometry identified heterochromatin protein 1γ (HP1γ) as a novel target for HIPK2. HIPK2 interaction with HP1γ induced phosphorylation of HP1γ, triggered release of HP1γ from histone H3K9me3 and suppressed γH2A.X accumulation. Our results revealed the possibility as HIPK2 may regulate global gene expression through chromatin remodeling in colon cancer cells.

Research Products

• [Journal Article] Transformer 2β and miR-204 regulate apoptosis through competitive binding to 3’UTR of BCL2 mRNA. (2015)
  • Author(s): Kuwano Y, Nishida K, Kajita K, Satake Y, Akaike Y, Fujita K, Kano S, Masuda K, Rokutan K.
  • Journal Title: Cell Death Differ. Volume: 22 (5) Issue: 5 Pages: 815-825
  • DOI: 10.1038/cdd.2014.176
  • Peer Reviewed / Open Access
• [Journal Article] Novel PAX9 mutations cause nonsyndromic tooth agenesis in Japanese patients (2014)
  • Author(s): Mitsui SN, Y asue A, Masuda K, Watanabe K, Horiuchi S, Imoto I, T anaka E
  • Journal Title: J Dent Res Volume: 93(3) Issue: 3 Pages: 245-249
  • DOI: 10.1177/0022034513519801
  • Peer Reviewed
• [Journal Article] HuR regulates alternative splicing of the TRA2 β gene in human colon cancer cells under oxidative stress. (2014)
  • Author(s): Akaike Y, Masuda K, Kuwano Y, Nishida K, Kajita K, Kurokawa K, Satake Y, Shoda K, Imoto I, Rokutan K.
  • Journal Title: Mol Cell Biol Volume: 34 Issue: 15 Pages: 2857-73
  • DOI: 10.1128/mcb.00333-14
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] HER2 amplification detected in the circulating DNA of patients with gastric cancer: a retrospective pilot study (2014)
  • Author(s): Shoda K, Masuda K, Ichikawa D, Arita T, Miyakami Y, Watanabe M, Konishi H, Imoto I, Otsuji E
  • Journal Title: Gastric Cancer. Volume: -
  • NAID: 40020631406
  • Peer Reviewed
• [Journal Article] Homeodomain-interacting protein kinase 2 regulates DNA damage response through interacting with heterochromatin protein 1γ. (2014)
  • Author(s): Akaike Y, Kuwano Y, Nishida K, Kurokawa K, Kajita K, Kano S, Masuda K, Rokutan K.
  • Journal Title: Oncogene. Volume: - Issue: 26 Pages: 3463-3473
  • DOI: 10.1038/onc.2014.278
  • Peer Reviewed / Open Access
• [Journal Article] Downregulation of serine/arginine-rich splicing factor 3 induces G1 cell cycle arrest and apoptosis in colon cancer cells. (2014)
  • Author(s): Kurokawa K, Akaike Y, Masuda K, Kuwano Y, Nishida K, Yamagishi N, Kajita K, Tanahashi T, Rokutan K.
  • Journal Title: Oncogene. Volume: 33 Issue: 11 Pages: 1407-17
  • DOI: 10.1038/onc.2013.86
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Chronic inhibition of tumor cell-derived VEGF enhances the malignant phenotype of colorectal cancer cells. (2013)
  • Author(s): Yamagishi N, Teshima-Kondo S, Masuda K, Nishida K, Kuwano Y, Dang DT, Dang LH, Nikawa T, Rokutan K.
  • Journal Title: BMC Cancer Volume: 13 Issue: 1 Pages: 229-229
  • DOI: 10.1186/1471-2407-13-229
  • Peer Reviewed
• [Journal Article] Application of DNA microarray technology to gerontological studies. (2013)
  • Author(s): Masuda K, Kuwano Y, Nishida K, Rokutan K.
  • Journal Title: Methods Mol Biol. Volume: 1048. Pages: 285-308
  • DOI: 10.1007/978-1-62703-556-9_19
  • ISBN: 9781627035552, 9781627035569
  • Peer Reviewed
• [Journal Article] NF90 in posttranscriptional gene regulation and microRNA biogenesis. (2013)
  • Author(s): Masuda K, Kuwano Y, Nishida K, Rokutan K, Imoto I.
  • Journal Title: Int J Mol Sci. Volume: 14(8) Issue: 8 Pages: 17111-21
  • DOI: 10.3390/ijms140817111
  • Peer Reviewed
• [Journal Article] Chronic academic stress increases a group of microRNAs in peripheral blood (2013)
  • Author(s): Honda M, Kuwano Y, Katsuura-Kamano S, Kamezaki Y, Fujita K, Akaike Y, Kano S, Nishida K, Masuda K, Rokutan K
  • Journal Title: PLoS One Volume: 8(10) Issue: 10 Pages: e75960-e75960
  • DOI: 10.1371/journal.pone.0075960
  • Peer Reviewed
• [Journal Article] Truncated serine/arginine-rich splicing factor 3 accelerates cell growth through up-regulating c-Jun expression (2013)
  • Author(s): Kano S, Nishida K, Nishiyama C, Akaike Y, Kajita K, Kurokawa K, Masuda K, Kuwano Y, Tanahashi T, Rokutan K
  • Journal Title: J Med Invest Volume: 60 Pages: 220-235
  • NAID: 130004822687
  • Peer Reviewed
• [Journal Article] Ets1 and heat shock factor 1 regulate transcription of the Transformer 2β gene in human colon cancer cells. (2013)
  • Author(s): Kajita K, Kuwano Y, Kitamura N, Satake Y, Nishida K, Kurokawa K, Akaike Y, Honda M, Masuda K, Rokutan K.
  • Journal Title: J Gastroenterol. Volume: 48(11) Issue: 11 Pages: 1222-33
  • DOI: 10.1007/s00535-012-0745-2
  • Peer Reviewed
• [Journal Article] General RBP expression in human tissues as a function of age (2012)
  • Author(s): Masuda K, et al.
  • Journal Title: Ageing Res Rev Volume: 11(4) Issue: 4 Pages: 423-31
  • DOI: 10.1016/j.arr.2012.01.005
  • Peer Reviewed
• [Journal Article] Role of miR-19b and its target mRNAs in 5-fluorouracil resistance in colon cancer cells (2012)
  • Author(s): Kurokawa K, Tanahashi T, Iima T, Yamamoto Y, Akaike Y, Nishida K, Masuda K, Kuwano Y, Murakami Y, Fukushima M, Rokutan
  • Journal Title: J Gastroenterol Volume: 47 Issue: 8 Pages: 883-895
  • DOI: 10.1007/s00535-012-0547-6
  • NAID: 10031051201
  • Peer Reviewed
• [Journal Article] MicroRNAs miR-144/144* and miR-16 in peripheral blood are potential biomarkers for naturalistic stress in healthy Japanese medical students. (2012)
  • Author(s): Katsuura S, Kuwano Y, Yamagishi N, Kurokawa K, Kajita K, Akaike Y, Nishida K, Masuda K, Tanahashi T, Rokutan K.
  • Journal Title: Neurosci Lett. Volume: 516 Issue: 1 Pages: 79-84
  • DOI: 10.1016/j.neulet.2012.03.062
  • Peer Reviewed
• [Journal Article] Heterogeneous Nuclear Ribonucleoprotein C1/C2 Controls the Metastatic Potential of Glioblastoma by Regulating PDCD4 (2012)
  • Author(s): Park YM, et al.
  • Journal Title: Mol Cell Biol Volume: 32 Issue: 20 Pages: 4237-4244
  • DOI: 10.1128/mcb.00443-12
  • Peer Reviewed
• [Presentation] 転写後調節異常による老化関連疾患の発症機構の解明 (2014)
  • Author(s): 増田清士
  • Organizer: 脳心血管抗加齢研究会2014
  • Place of Presentation: 梅田スカイビル（大阪府大阪市）
  • Year and Date: 2014-12-06 – 2014-12-07
  • Invited
• [Presentation] A novel RNA binding protein, SSP-1, induced cell growth in squamous cell carcinoma modulating cancer-associated gene expression in posttranscriptional mechanism (2014)
  • Author(s): Masuda K, Shoda K, Hamada J, Imoto I
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] An RNA binding protein, SSP1, induced cell growth in squamous cell carcinoma through posttranscriptional regulation (2014)
  • Author(s): Masuda K, Shoda K, Hamada J, Imoto I
  • Organizer: Cell Symposia Regulatory RNAs
  • Place of Presentation: バークレー（アメリカ）
  • Year and Date: 2014-10-19 – 2014-10-21
• [Presentation] Transformer 2β and miR-204 regulate cell death through competitive binding to 3' UTR of BCL2 mRNA (2014)
  • Author(s): Kuwano Y, Satake Y, Kano S, Fujita K, Itai M, Nishida K, Naruto T, Masuda K, Rokutan K
  • Organizer: Cell Symposia Regulatory RNAs
  • Place of Presentation: バークレー（アメリカ）
  • Year and Date: 2014-10-19 – 2014-10-21
• [Presentation] Analysis of functional transcribed-ultraconserved regions of SR protein family (2014)
  • Author(s): Kano S, Nishida K, Satake Y, Fujita K, Itai M, Naruto T, Masuda K, Kuwano Y, Rokutan K
  • Organizer: Cell Symposia Regulatory RNAs
  • Place of Presentation: バークレー（アメリカ）
  • Year and Date: 2014-10-19 – 2014-10-21
• [Presentation] A novel RNA binding protein, SSP1, induced cell growth in squamous cell carcinoma through posttranscriptional regulation (2014)
  • Author(s): 増田清士、庄田勝俊、濵田隼一、井本逸勢
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] RNA結合蛋白質による転写後調節機構の異常と消化器がん発症機構の解明 (2014)
  • Author(s): 増田清士、西田憲生、六反一仁、井本逸勢
  • Organizer: 第100回日本消化器病学会総会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2014-04-23 – 2014-04-26
• [Presentation] 選択的スプライシング制御因子SRSF3による大腸がん細胞の悪性形質変化誘導の解明 (2013)
  • Author(s): 増田清士、西田憲生、六反一仁、井本逸勢
  • Organizer: 第21回日本消化器関連学会週間
  • Place of Presentation: グランドプリンスホテル新高輪・国際館パミール・グランドプリンスホテル高輪（東京都）
• [Presentation] RNA結合蛋白質HuRによる選択的スプライシング制御機構の解明 (2013)
  • Author(s): 増田清士、赤池瑶子、庄田勝俊、村田知慧、桑野由紀、西田憲生、田嶋敦、井本逸勢
  • Organizer: 第29回日本ストレス学会学術総会
  • Place of Presentation: 徳島大学大塚講堂（徳島県）
• [Presentation] 新規RNA結合蛋白質による食堂扁平上皮がんの発がん機構の解明 (2013)
  • Author(s): 増田清士、西田憲生、六反一仁、井本逸勢
  • Organizer: 第100回日本消化器病学会四国支部例会
  • Place of Presentation: アルファあなぶきホール（香川県）
• [Presentation] HuR stimulates cell growth in colon cancer cells by regulating alternative splicing under oxidative stress (2013)
  • Author(s): 増田清士、赤池瑶子、庄田勝俊、村田知慧、田嶋敦、桑野由紀、西田憲生、六反一仁、井本逸勢
  • Organizer: 第３６回日本分子生物学会年会
  • Place of Presentation: 神戸国際会議場・神戸国際展示場・神戸ポートピアホテル（兵庫県）
• [Presentation] Hu antigen R (HuR) Regulates an Alternative Splicing of Transformer 2-beta (Tra2beta) and Induces lncRNA (Tra2beta4) under Oxidative Stress (2012)
  • Author(s): 増田清士 他
  • Organizer: Cell Symposia Regulatory RNAs
  • Place of Presentation: Hotel Melia （スペイン）
• [Presentation] アドリアマイシンによる、選択的スプライシング制御を介した新たな腫瘍抑制分子機構 (2012)
  • Author(s): 増田清士 他
  • Organizer: 第97回日本消化器病学会四国支部例会
  • Place of Presentation: あわぎんホール（徳島県）
• [Presentation] 選択的スプライシング調節因子SRSF3によるG1/Sチェックポイントとアポトーシスの制御機構 (2012)
  • Author(s): 黒川憲 他
  • Organizer: 第97回日本消化器病学会四国支部例会
  • Place of Presentation: あわぎんホール（徳島県）
• [Presentation] PTC-containing TRA2b4 mRNAによるp21の転写調節を介した細胞老化の制御 (2012)
  • Author(s): 梶田敬介 他
  • Organizer: 第97回日本消化器病学会四国支部例会
  • Place of Presentation: あわぎんホール（徳島県）
• [Presentation] 酸化ストレス下での、HuRによるtransformer 2-beta（Tra2b）の選択的スプライシング制御機構 (2012)
  • Author(s): 赤池瑤子 他
  • Organizer: 第97回日本消化器病学会四国支部例会
  • Place of Presentation: あわぎんホール（徳島県）
• [Presentation] Hu antigen R (HuR) Functions as An Alternative Splicing Regulator of Transformer 2-beta (TRA2beta) in response to Oxidative Stress (2012)
  • Author(s): 赤池瑤子 他
  • Organizer: the 4th EMBO meeting
  • Place of Presentation: Nice Acropolis（フランス）
• [Presentation] 酸化ストレスにおける選択的スプライシング制御異常と消化器がん発症機構の解明 (2012)
  • Author(s): 増田清士 他
  • Organizer: 第20回日本消化器関連学会週間
  • Place of Presentation: 神戸国際展示場・ポートピアホテル・神戸国際会議場（兵庫県）
• [Presentation] The Homeodomain-interacting protein kinase 2 (HIPK2) interacts with heterochromatin protein 1g (HP1g) and regulates DNA repair (2012)
  • Author(s): 赤池瑤子 他
  • Organizer: 第7回臨床ストレス応答学会大会
  • Place of Presentation: 東京女子医科大学 弥生記念講堂（東京都）
• [Presentation] homeodomain-interacting protein kinase -2 (HIPK2)はheterochromatin-like protein 1 g (HP1g)と相互作用しDNA修復を制御する (2012)
  • Author(s): 赤池瑤子 他
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡(福岡県）