Yoshiaki ITO

Senior Principal Investigator, Cancer Science Institute of Singapore, NUS
Yong Loo Lin Professor in Medical Oncology, NUS

csiitoy[at]nus.edu.sg

Dr. Ito’s research is in the elucidation of the molecular mechanism of carcinogenesis. He discovered the major oncoprotein of polyomavirus, middle T antigen which is a membrane bound protein.  This discovery indicated the importance of cell surface as the site to initiate cancer development.  Structure of middle T antigen was later found to be mimicking activated growth factor receptor.  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.  Furthermore, he discovered that RUNX genes have important roles in tissue stem cell which is cell of origin of cancer.

Research

In 1993, three groups headed by Misao Ohki, Peter Gergen and myself reported a new class of transcription factor family, now called the RUNX family (Trends in Genetics). RUNX genes are essential developmental regulators, frequently involved in cancer and encode transcription factors. Since its discovery, our group has been studying the roles of the RUNX family, especially on RUNX3, in carcinogenesis. We found that RUNX genes have dual roles, tumor suppressive or oncogenic, depending on the cell context. At early stages of investigations, RUNX1 was found to be essential for generation of hematopoietic stem cells, with RUNX1 gene mutations prevalent in leukemia. RUNX2 is required for maturation of osteoblast, but has been linked to breast and prostate metastasis. RUNX3 exerts strong tumor suppressive effects in multiple tissues, such as gastrointestinal tract, lung and breast. Epigenetic inactivation of RUNX3 is frequent in solid tumors. Recently, an exciting new concept of RUNX1 as a key regulator of adult stem cells in multiple organs has emerged. Furthermore, our findings also indicate an important role for RUNX3 in such adult stem cells. Currently, our major interest is to uncover the roles of RUNX genes in adult stem cells and how these roles are deregulated when adult stem cells are reprogrammed to cancer cell-of-origin.

Historical flow of our research activities:

Using mouse model, we found that knockout of Runx3 induces adenoma in the intestine, lung, mammary gland as well as precancerous lesions in the stomach. This is the cornerstone of our argument that Runx3 is a tumor suppressor and gatekeeper of cancer development. We have linked Runx3 with key effectors of major signalling pathways in cancer: Runx3 interacts with TCF4/?-catenin complex, YAP/TEAD4 complex, and STAT3 and 5 to inhibit their oncogenic activities. Conversely, the expression of RUNX1, 2 and 3 – some times at high levels – in human gastric cancer suggests that RUNX might function as oncogene. At present we do not know the molecular mechanism of how RUNX switches between its dual function of tumor suppressor and oncogene. But, we have a clue from human gastric cancer: we found that a single nucleotide change R122C in RUNX3 results in its conversion from tumor suppressor to oncogene (Cell 2002). To study the underlying mechanism, we generated a mouse model harbouring the R122C mutation. The stomach of this mouse is precancerous with a dramatic increase of stomach isthmus stem cells. We are intensely studying this mouse model to find out how a single amino acid change could convert normal stem cells to a precancerous state.

Another frontier in our group is our research on adult stem cells, since they are considered to be the origin of cancer cells. Runx1 enhancer element, eR1, is 270 bp and was originally observed to drive Runx1 expression in hematopoietic stem cells. Recently, we found that eR1 also functions in adult stem cells in multiple organs, indicating its unique specificity for stem cells of diverse tissues. Using eR1, we identified rapidly proliferating stomach stem cells located at isthmus (Gastroenterology 2017). In addition, there is another type of stem cells in stomach – dormant, reserve stem cells – present at the base of gland. We found that these two types of stem cells are necessary for homeostasis of the tissue and they are profoundly related. We discovered a protein that specifically functions in rapidly proliferating stem cells. This protein is also necessary for proliferation of cancer cells. We are interested in finding out how the signal transduction machinery that specifically operates in normal adult stem cells are hijacked in cancer cells.

Lab Members

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.</span

Honors & Awards

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