Yoshiaki ITO

RUNX genes are evolutionarily conserved, developmental regulator genes found in the metazoan phyla. They encode the DNA-binding subunit of the transcription factor PEBP2/CBF, also known as the Runt- domain transcription factor. Being ancient genes subjected to multiple evolutionary changes, the RUNX family is involved in diverse but fundamental biological activities. There are three mammalian RUNX genes, RUNX1, RUNX2 and RUNX3, all of which are associated with oncogenic activities. While RUNX3 is a key tumor suppressor in many tissue types such as gastric, colon and bladder, it promotes oncogenesis in ovarian and skin cancers.

In Runx3-deficient mice, loss of chief cells and development of metaplasia are observed resembling a subset of precancerous state associated with human gastric cancer.

Over the years, my laboratory has found that RUNX3 contributes in multiple ways to bolster the protective barrier that prevents normal cells from succumbing to malignancy. We will study the molecular mechanisms and clinical aspects using mouse models and gastric cancer xenografts in immunocompromized mice.

RUNX genes are evolutionarily conserved, developmental regulator genes found in the metazoan phyla. They encode the DNA-binding subunit of the transcription factor PEBP2/CBF, also known as the Runt- domain transcription factor. Being ancient genes subjected to multiple evolutionary changes, the RUNX family is, not surprisingly, involved in diverse but fundamental biological activities. There are three mammalian RUNX genes, RUNX1, RUNX2 and RUNX3, all of which are associated with oncogenic activities. Curiously, RUNX3 plays dualistic roles in carcinogenesis. While it is a key tumor suppressor in many tissue types such as gastric, colon and bladder, it promotes oncogenesis in ovarian and skin cancers.

In the gastric epithelium, Runx3 functions as a mediator of the TGF- pathway and modulates cellular proliferation and apoptosis through transcriptional regulation of genes, such as cell cycle regulator, p21WAF1 and the proapoptotic gene BIM-1, respectively (Li et al, 2002; Chi et al, 2005; Yamamura et al, 2006; Yano et al, 2006). In Runx3-deficient mice, the loss of these functions results in hyperproliferation in the gastric epithelium due to dysregulated cell growth and the impairment of TGF-β-mediated apoptosis (Li et al, 2002). This is accompanied by gross intestinalization, loss of chief cells and development of metaplasia, resembling a subset of precancerous state associated with human gastric cancer (Ito et al, 2011).

Consistent with its tumor suppressor activities, the loss of RUNX3 function is observed in up to 80% of human gastric cancer due to epigenetic silencing by promoter hypermethylation and protein mislocalization (Li et al, 2002, Ito et al, 2005). Immortalized cell lines established from Runx3-/-.p53-/- fetal mouse gastric epithelia are tumorigenic when transplanted into nude mice, but not their Runx3+/+.p53-/- counterpart (Li et al, 2002; Ito et al, 2011).

RUNX3 also functions as a negative regulator of the Wnt pathway by binding to the TCF/b-catenin complex to prevent DNA binding (Ito et al, 2008; Ito et al, 2011). In mouse, this relationship is reflected in the increased intestinal tumor incidence and malignancy in Runx3+/-.Apcmin/+ compound mutant mice, compared with mice bearing single mutations (Ito et al, 2008). In human, the RUNX3R122C mutation identified in human gastric cancer is unable to attenuate the Wnt signal (Ito et al, 2011).

Over the years, my laboratory has found that RUNX3 contributes in multiple ways to bolster the protective barrier that prevents normal cells from succumbing to malignancy. We have identified at least three widely different areas where RUNX3 may function prominently as “gatekeeper”: Epithelial Mesenchymal Transition, DNA Damage Response and Centrosome function. We will study the molecular mechanisms and clinical aspects using mouse models and gastric cancer xenografts in immunocompromized mice.

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Selected Publications:

  1. Ito Y, Bae SC, Chuang LSH. The RUNX Family: Developmental Regulators in Cancer. Nature Reviews Cancer. 2015;15(2):81-95.
  2. Hor YT, Voon DCC, Koo JKW, Wang H, Lau WM, Ashktorab H, Chan SL, Ito Y. A Role for RUNX3 in Inflammation-Induced Expression of IL23A in Gastric Epithelial Cells. Cell Reports. 2014;8(1):50-8.
  3. Wang CQ, Krishnan V, Tay LS, Chin DWL, Koh CP, Chooi JY, Nah GSS, Du L, Jacob B, Yamashita N, Lai SK, Tan TZ, Mori S, Tanuichi I, Tergaonkar V, Ito Y, Osato M. Disruption of Runx1 and Runx3 Leads to Bone Marrow Failure and Leukemia Predisposition due to Transcriptional and DNA Repair Defects. Cell Reports. 2014;8(3):767-82.
  4. Ito K, Chuang LS, Ito T, Chang TL, Fukamachi H, Salto-Tellez M, Ito Y. Loss of Runx3 is a key event in inducing precancerous state of the stomach. Gastroenterology. 2011 Jan;140:1536-1546
  5. Ito K, Lim AC, Salto-Tellez M, Motoda L, Osato M, Chuang LS, Lee CW, Voon DC, Koo JK, Wang H, Fukamachi H, Ito Y. RUNX3 Attenuates beta-Catenin/T Cell Factors in Intestinal Tumorigenesis. Cancer Cell. 2008 Sep 9; 14(3): 226-37.
  6. Ito K, Liu Q, Salto-Tellez M, Yano T, Tada K, Ida H, Huang C, Shah N, Inoue M, Rajnakova A, Hiong KC, Peh BK, Han HC, Ito T, Teh M, Yeoh KG, Ito Y. RUNX3, a novel tumor suppressor, is highly inactivated in gastric cancer by protein mislocalization. Cancer Res. 2005 Sep 1; 65(17): 7743-50.
  7. Taniuchi I, Osato M, Egawa T, Sunshine MJ, Bae SC, Komori T, Ito Y, Littman DR. Differential requirements for Runx proteins in CD4 repression and epigenetic silencing during T lymphocyte development. Cell. 2002 Nov 27; 111(5): 621-33.
  8. Li QL, Ito K, Sakakura C, Fukamachi H, Inoue K, Chi XZ, Lee KY, Nomura S, Lee CW, Han SB, Kim HM, Kim WJ, Yamamoto H, Yamashita N, Yano T, Ikeda T, Itohara S, Inazawa J, Abe T, Hagiwara A, Yamagishi H, Ooe A, Kaneda A, Sugimura T, Ushijima T, Bae SC, Ito Y. Casual Relationship between the Loss of RUNX3 Expression and Gastric Cancer. Cell. 2002 Apr 5; 109(1): 113-24.
  9. Ogawa E, Maruyama M, Kagoshima H, Inuzuka M, Lu J, Satake M, Shigesada K, Ito Y. PEBP2/PEA2 represents a family of transcription factors homologous to the products of the Drosophila runt gene and the human AML1 gene. Proc Natl Acad Sci USA. 1993 Jul 15; 90(14): 6859-63.
  10. Smart, J. E., and Ito, Y. Three species of polyoma virus tumor antigens share common peptides probably near the amino termini of the proteins. Cell (1978) 15, 1427-1437.
Name Yoshiaki ITO
Affiliations Senior Principal Investigator, Cancer Science Institute of Singapore, NUS
Yong Loo Lin Professor in Medical Oncology, NUS
Email csiitoy[at]nus.edu.sg

Research Interest

Dr. Ito’s research is in the elucidation of the molecular mechanism of carcinogenesis. He discovered the major oncoprotein of polyomavirus, middle T antigen that triggered the discovery of well known tumor suppressor, p53. More recently, his group identified RUNX transcription factors that are critical regulators of development and cancer, reported RUNX2 cDNA sequence for the first time and became a major contributor to establish the RUNX field. Most recently, he discovered RUNX3 is a tumor suppressor of gastric, colon and many other solid tumors.

Education

Institute Degree (if applicable) Year(s)
Tohoku University, School of Medicine, Sendai, Japan MD 1963
Tohoku University, Graduate School of Medical Sciences, Sendai, Japan Ph.D. 1968

Professional Experience

Programme Leader and Senior Principal Investigator, Cancer Science Institute of Singapore, National University of Singapore 2008 – Present
Professor of Medical Oncology, Yong Loo Lin School of Medicine, National University of Singapore 2002 – Present
Deputy Director, Cancer Science Institute of Singapore, National University of Singapore 2008 – 2012
Director, Oncology Research Institute (ORI), National University of Singapore, Principal Investigator, Professor, IMCB, A*STAR Singapore 2002 – 2008
Director, Institute for Virus Research Kyoto University, Kyoto, Japan 1995 – 2001
Professor, Laboratory of Cell Regulation, Department of Viral Oncology Institute for Virus Research, Kyoto University, Kyoto, Japan 1984 – 2002
Head, Cell Transformation Section, Basic Science Program, National Cancer Institute, Frederick Cancer Research Facility, Frederick, Maryland, USA 1983 – 1984
Visiting Scientist, National Institute of Allergy and Infections Diseases, National Institute of Health Bethesda, Maryland, USA 1979 – 1983
Scientific Staff, Department of Cell Regulation, Imperial Cancer Research Fund Laboratories, London, England 1975 – 1979
Research Fellow, Department of Cell Regulation Imperial Cancer Research Fund Laboratories, London, England (in the laboratory of Dr. Renato Dulbecco) 1972 – 1974
Research Associate, Department of Microbiology and Immunology, Duke University Medical Center, North Carolina, USA (in the laboratory of Dr. Wolfgang K. Joklik) 1969 – 1972
Instructor, Department of Bacteriology, School of Medicine, Tohuku University, Sendal, Japan 1968 – 1969

CHUANG Shyue Huey, Linda

PhD
Senior Research Scientist

RUNX transcription factors.

Junichi MATSUO

PhD
Research Scientist

Role of Runx1 in stomach epithelium.

Arun Kumar Kolinjivadi CHANDRA

PhD
Research Fellow

Dissecting the role of RUNX genes in maintaining genome integrity.

CUI Jianzhou

PhD
Research Fellow

Focus on gene modulation in carcinogenesis related to RAS pathway.

Daisuke DOUCHI

PhD
Research Fellow

Investigating the role of RUNX genes in carcinogenesis.

LIM Kee Siang

PhD
Research Fellow

Investigate the novel function of epithelial IL-23A in gastric cancer.

Naing Naing MON

MBBS, PhD
Research Fellow

Investigation of possible roles of RUNX genes involved in carcinogenesis through p53 pathway.

Khine Nyein MYINT

MBBS, PhD
Research Fellow

Investigating the roles of RUNX in mitosis and carcinogenesis.

Kazuto SUDA

PhD
Research Fellow

Investigate the function of cancer stem cells.

Debbie LIM Xiu En

Research Assistant

Investigate the role of PARP inhibitors that can induce synthetic lethality in BRCA gene mutated gastric cancer cells.

Nur Astiana BTE MAWAN

Laboratory Executive

Characterizing the function of RUNX3 in mitosis via the identification of proteins that interact with RUNX3.

LIM Yi Hui Melissa

Laboratory Executive

Role of Runx genes in carcinogenesis.

President Science Award, Singapore 2010
Tomizo Yoshida Prize, Japanese Cancer Association 2003
Princess Takamatsu Cancer Research Award, Princess Takamatsu Cancer Research Foundation, Japan 1995
Kuroya Award, Japanese Society for Microbiology 1968