Directory

Duke-NUS Medical School
Directory

Koji Itahana

Associate Professor

Laboratory of Tumor Suppression

Bio Research Publications

Dr. Itahana obtained his B.S. and Ph.D. degree at the Faculty of Science, Kyoto University in Japan. He subsequently received postdoctoral training at the laboratory of Dr. Judith Campisi, Lawrence Berkeley National Laboratory to study the role for p53 in cellular senescence, and at the laboratory of Dr. Yanping Zhang, University of North Carolina at Chapel Hill to study the role for ARF-MDM2-p53 pathway in tumor suppression. After he started his own laboratory at Cancer & Stem Cell Biology Programme, Duke-NUS Medical School in Oct, 2009, he identified a number of targets and modulators in ARF-MDM2-p53 pathway to reveal several novel non-canonical functions of ARF-MDM2-p53 pathway in preventing tumorigenesis, including those involved in cancer metabolism. He is currently an Associate Professor at Duke-NUS Medical School, and he continues to work on the functions of ARF and p53 as well as cancer metabolism.

The primary goal of our laboratory is to develop novel therapeutic strategies against cancer by investigating ARF-MDM2-p53 tumor suppressive mechanisms and cancer metabolism.

Revealing non-canonical functions of ARF-MDM2-p53 pathway

ARF-MDM2-p53 pathway is a well-known tumor suppressive pathway which must be abrogated for cells to become cancerous. My postdoctoral research projects focused on this pathway, revealing new functions of ARF such as inhibiting ribosome biogenesis by degrading NPM1 (Itahana K et al. 2003) and inducing apoptosis by a collaboration with p32 by localizing in mitochondria (Itahana K et al. 2008). I also showed that an E3 ligase activity of MDM2 is critical for regulating p53, but not for MDM2 self-ubiquitination, by utilizing an E3-deficient Mdm2 knock-in mouse model (Itahana K et al. 2007).

Several recent knock-in mouse models that lack canonical functions of p53 have challenged the long-held view that these canonical functions mediate tumor suppression by p53 and highlighted the importance of non-canonical, diverse roles of the p53 tumor suppressor. Yet, little is known about these new functions of p53 and their mediators, and how they contribute to tumor suppression. Therefore, our laboratory has focused on uncovering novel non-canonical functions of this pathway by searching for new downstream targets of p53 and new binding proteins of ARF and p53. We demonstrated a novel role of ARF in preventing genomic instability caused by centrosome amplification (Neo S et al. 2015). We revealed the unique epigenetic strategies in human embryonic stem cells (hESCs) that control p53 target gene expression for maintaining homeostasis and genomic stability in ESCs (Itahana Y et al. 2017). We also revealed new roles for p53 in response to histone methylation inhibitor (Cheng L et al. 2012) and to irradiation in quiescent cells (Dai J et al. 2015). Our other ongoing research projects include the mechanism of mutant p53-mediated promotion of metastasis and the ability of ARF to enhance immune response.

Revealing a potential strategy targeting cancer metabolism

The second focus of our laboratory is studying cancer metabolism. It is well known that cancers have unique metabolic profiles which may promote cancer development and cause chemotherapy resistance in cancers. These unique metabolic properties of cancer cells can be therapeutically targeted. We studied the effects of the loss of p53 that causes changes in metabolic profiles, such as uncontrolled ROS production and reduced autophagy. We demonstrated the first beneficial link between p53 and uric acid for an antioxidant function to prevent cancer (Itahana Y et al. 2015). We also identified that p53-TGM2 pathway is a critical barrier to prevent oncogenic transformation by promoting autophagy (Yeo et al. 2016). Our other ongoing research projects include the finding of the critical role for PP2A in glucose metabolism in cancer and identification of unique metabolism in bats that contributes to cancer prevention and sustaining their longevity.

Mutant TP53 interacts with BCAR1 to contribute to cancer cell invasion.

Guo AK, Itahana Y, Seshachalam VP, Chow HY, Ghosh S, Itahana K (2020)

Br J Cancer. doi: 10.1038/s41416-020-01124-9 [online ahead of print]

Potassium channel dysfunction in human neuronal models of Angelman syndrome.

Sun AX, Yuan Q, Fukuda M, Yu W, Yan H, Lim GGY, Nai MH, D'Agostino GA, Tran HD, Itahana Y, Wang D, Lokman H, Itahana K, Lim SWL, Tang J, Chang YY, Zhang M, Cook SA, Rackham OJL, Lim CT, Tan EK, Ng HH, Lim KL, Jiang YH, Je HS (2019)

Science 366:6472:1486-1492

ABCB1 protects bat cells from DNA damage induced by genotoxic compounds.
Koh J, Itahana Y, Mendenhall IH, Low D, Soh EXY, Guo AK, Chionh YT, Wang LF*, Itahana K* (2019)
Nat Commun. 10:1:2820 (*co-corresponding authors)

High basal heat-shock protein expression in bats confers resistance to cellular heat/oxidative stress.
Chionh YT, Cui J, Koh J, Mendenhall IH, Ng JHJ, Low D, Itahana K, Irving AT, Wang LF (2019)
Cell Stress Chaperones 24:4:835-849

Tumor suppressor p14ARF enhances IFNγ-activated immune response by inhibiting PIAS1 via SUMOylation.
Alagu J, Itahana Y, Sim F, Chao SH, Bi X, Itahana K (2018)
J Immunol. pii: ji1800327

Ca2+-dependent PP2Ac demethylation promotes cancer cell death in response to glucose deprivation independently of inhibiting glycolysis.
Lee HY, Itahana Y, Schuechner S, Fukuda M, Je HS, Ogris E, Virshup DM, Itahana K (2018)
Sci Signal. 11:512, pii: eaam7893

Emerging Roles of p53 Family Members in Glucose Metabolism.
Itahana Y, Itahana K (2018)
Int J Mol Sci. 19:3, pii: E776 (review)

p32 regulates ER stress and lipid homeostasis by down-regulating GCS1 expression.
Liu Y, Leslie PL, Jin A, Itahana K, Graves LM, Zhang Y (2018)
FASEB J. fj201701004RR

p32 heterozygosity protects against age- and diet-induced obesity by increasing energy expenditure.
Liu Y, Leslie PL, Jin A, Itahana K, Graves LM, Zhang Y (2017)
Sci Rep.18:7:1:5754.

Histone modifications and p53 binding poise the p21 promoter for activation in human embryonic stem cells.
Itahana Y*, Zhang J*, Göke J, Vardy LA, Han R, Iwamoto K, Engin C, Robson P, Pouladi MA, Colman A**,Itahana K** (2016)
Sci Rep. 6:28112 (*equal contribution) (**co-corresponding authors)

Germline hemizygous deletion of CDKN2A-CDKN2B locus in a patient presenting with Li-Fraumeni syndrome.
Chan SH, Lim WK, Michalski S, Lim JQ, Ishak ND, Met-Domestici M, Ng CCY, Vikstrom K, Esplin ED, Fulbright J, Ang MK, Wee J, Sittampalam K, Farid M, Lincoln SE, Itahana K, Abdullah S, Teh BT, Ngeow J (2016)
npj Genomic Medicine 1:16015

Transglutaminase 2 (TGM2) contributes to a p53-induced autophagy program to prevent oncogenic transformation.
Yeo SY*, Itahana Y*, Guo AK, Han R, Iwamoto K, Nguyen TH, Bao Y, Kleiber K, Wu YJ, Bay BH, Voorhoeve PM**, Itahana K** (2016)
eLife 5:e07101 (*equal contribution) (**co-corresponding authors)

TRIM28 is an E3 ligase for ARF-mediated NPM1/B23 SUMOylation that represses centrosome amplification.
Neo SH*, Itahana Y*, Alagu J, Kitagawa M, Guo A, Lee SH, Tang K, Itahana K (2015)
Mol Cell Biol. 35:16:2851-2863 (*equal contribution)

Quiescence does not affect p53 and stress response by irradiation in human lung fibroblasts.
Dai J, Itahana K*, Baskar R* (2015)
Biochem Biophys Res Commun 458:1:104-109 (*co-corresponding authors)

The uric acid transporter SLC2A9 is a direct target gene of the tumor suppressor p53 contributing to antioxidant defense.
Itahana Y, Han R, Barbier S, Lei Z, Rozen S, Itahana K (2015)
Oncogene 34:14:1799-1810

Colorimetric detection of senescence-associated β galactosidase.
Itahana K, Itahana Y, Dimri GP. (2013)
Methods Mol Biol. 965:143-156

TP53 genomic status regulates sensitivity of gastric cancer cells to the histone methylation inhibitor 3-Deazaneplanocin A (DZNep)
Cheng LL, Itahana Y, Lei ZD, Chia NY, Wu Y, Yu Y, Zhang SL, Thike AA, Pandey A, Rozen S, Voorhoeve PM, Yu Q, Tan PH, Bay BH, Itahana K*, Tan P* (2012).
Clin Cancer Res. 18:15:4201-4212 (*co-corresponding authors)

Emerging roles of mitochondrial p53 and ARF.
Itahana Y, Itahana K (2012)
Curr Drug Targets. 13:13:1633-1640 (Review)

The diverse and complex roles of radiation on cancer treatment: therapeutic target and genome maintenance.
Baskar R, Yap SP, Chua KL, Itahana K (2012)
Am J Cancer Res. 2:4:372-382 (Review)

Mdm2 RING mutation enhances p53 transcriptional activity and p53-p300 interaction.
Clegg HV, Itahana Y, Itahana K, Ramalingam S, Zhang Y (2012)
PLoS One. 7:5:e38212

Depletion of guanine nucleotides leads to the Mdm2-dependent proteasomal degradation of nucleostemin.
Huang M, Itahana K, Zhang Y, Mitchell BS (2009)
Cancer Res. 69:7:3004-3012

Mitochondrial p32 is a critical mediator of ARF-induced apoptosis.
Itahana K and Zhang Y (2008)
Cancer Cell 13:6:542-553 (featured article)

Targeted inactivation of Mdm2 RING finger E3 ubiquitin ligase activity in the mouse reveals mechanistic insights into p53 regulation.
Itahana K, Mao H, Jin A, Itahana Y, Clegg H, Lindström MS, Bhat K, Godfrey VL, Evan GI, Zhang Y (2007)
Cancer Cell 12:4:355-366 (cover article, comment in Nature Reviews Cancer 2007, 7(12), 896)

Tumor suppressor ARF degrades B23, a nucleolar protein involved in ribosome biogenesis and cell proliferation.
Itahana K, Bhat KP, Jin A, Itahana Y, Hawke D, Kobayashi R, Zhang Y (2003)
Mol Cell. 12:5:1151-1164

Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1.
Itahana K, Zou Y, Itahana Y, Martinez JL, Beausejour C, Jacobs JJ, Van Lohuizen M, Band V, Campisi J, Dimri GP (2003)
Mol Cell Biol. 23:1:389-401

A role for p53 in maintaining and establishing the quiescence growth arrest in human cells.
Itahana K, Dimri GP, Hara E, Itahana Y, Zou Y, Desprez PY, Campisi J. (2002)
J Biol Chem. 277:20:18206-18214