Yoshiaki ITO

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

csiitoy[at]nus.edu.sg


Professor Ito’s research centers on the regulation of stem cells in the stomach.  Stem cells are required for daily maintenance of the stomach, which is constantly damaged by microorganisms and chemicals. The basis of our research was the discovery of a gene, RUNX3, that may act as either a cancer promoting (oncogene) or cancer suppressing gene (tumour suppressor). Through our research of the RUNX genes, we have revealed a new stem cell protein, which controls stem cell proliferation and tissue repair. This is important as cancer development is linked to disruption of these processes due to abnormal gene expression in so called “cancer stem cells”- a small subpopulation of cells within tumors with the potential to initiate tumor growth when transplanted into another host animal. Identification and study of these cells may reveal new insights into cancer development and potential cancer treatments or diagnostic tools.

Research

Historical flow of our research activities from RUNX to stem cells:

In 1993, three groups including my own reported a new class of transcription factor family, now called the RUNX family [Trends Genet 9:338-41,1993]. RUNX genes encode transcription factors that function as master developmental regulators. They are also frequently involved in cancer. Since their discovery, our group has been studying the roles of the RUNX family, especially RUNX3, in carcinogenesis. We found that RUNX genes have paradoxical roles, functioning as tumor suppressors or oncogenic drivers, depending on the cell context [Nat Rev Cancer 15:81-95, 2015]. Recently, an exciting new concept of RUNX as a key regulator of adult stem cells in multiple organs has emerged.

A 270 bp element of RUNX1 enhancer, termed eR1 [Stem Cells 28: 1869-81, 2010], is responsible for the specific expression of RUNX1 in hematopoietic stem cells. We subsequently found that eR1 also drives the expression of RUNX1 in tissue stem cells of multiple organs. Having developed eR1 as a powerful tool to study stem cells, we identified the elusive rapidly proliferating stomach isthmal epithelial stem cells [Gasroenterol 152:218-231, 2017]. We explored the protein and gene expression profiles of these isthmal stem cells and found strong enrichment of a cytoskeletal scaffold protein IQ3. This scaffold protein interacts with multiple proteins to enhance signaling intensity. Among them, the GTP bound form of Ras is particularly important, Furthermore, we found that IQ3 is expressed in the majority, if not all, of rapidly proliferating gastric cancer cells. A comparison with the expression of cancer stem cell marker indicated that that IQ3 expression may mark a rapidly proliferating population of cancer stem cells. The expression of IQ3 in multiple cancer types indicates a broad role for IQ3 in oncogenesis.

 

 

We are also studying how IQ3 is specifically expressed in stem cells and how IQ3 maintains stem cell property. Promising regulators of IQ3, including an RNA binding protein, have been identified. Depletion of IQ3 or its upstream regulators in stem cells or gastric cancer cells induced cellular differentiation, accompanied by sharp decreases of transcription of stem cell factors such as Oct4, Nanog and Sox2. IQ3 therefore has a capability to maintain the transcriptional signature of stem cells. This induction of differentiation in aggressive, poorly differentiated cancer cells indicates a novel area for therapeutic exploitation – development of inhibitors against IQ3 or its upstream regulators may lead to effective reprogramming of proliferating cancer stem cells and activation of the terminal differentiation process.

Another important aspect of IQ3 is its role in tissue repair. Soon after tissue damage, IQ3 is robustly induced in normally quiescent, fully differentiated zymogenic chief cells. This induction is associated with the reprogramming of chief cells, which acquire proliferative and stem-like properties. Furthermore, transcriptomic analysis of the damaged tissues revealed striking similarities to the gene expression signature of early gastric cancer. There is a classical observation that cancer is ‘a wound that does not heal’ [N Engl J Med 315:1650-9, 1986]. Therefore, coupled with the fact that IQ3 is strongly expressed in cancer cells, we propose that the IQ3-driven repair process is linked to the carcinogenic process and that we are observing the beginnings of cancer.

Aside from transcription regulation, we have also uncovered unexpected links of RUNX3 protein to the Fanconi anemia DNA repair pathway, TGF?-induced genomic instability and Aurora kinases during mitotic entry – all of which support the role RUNX3 as a primary line of defense against oncogenic stimuli [Cell Rep 24:1747-55, 2018; PNAS 113:6490-5, 2016; Cancer Res 78:88-102, 2018; Cell Rep 8:767-82, 2014].

Using mouse models, we found that knockout of RUNX3 induces adenoma in the intestine, lung, mammary gland as well as precancerous lesions in the stomach [Oncogene 29:2605-15, 2010; Gastroenterol 140:1536-46, 2011; Cancer Cell 14:226-237, 2008]. This is the cornerstone of our argument that RUNX3 is a tumor suppressor and gatekeeper of cancer development. RUNX3 can also function as an oncogene. We have excellent tool to solve this puzzle. We found that a single nucleotide change R122C in RUNX3, identified in a patient of gastric cancer, results in its conversion from tumor suppressor to oncogene [Cell 109: 113-24, 2002]. By introducing this single nucleotide change in the mouse genome, we are finding that RUNX3 has an important role in the cell cycle regulation in the adult stem 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