The focus of our laboratory is to investigate the mechanistic basis of chromatin regulation by chromatin enzymes (CE). The implications of CE in cancer has received rising attention following recent findings of high frequency of CE mutations in cancer and subsequent characterizations of CE mutations in Asian cancer types including cancer of stomach, bile duct, kidney and T-cell lymphoma. However, the functional mechanisms of CE and how their mutations contribute to tumorigenesis remain poorly understood. To address these questions, our studies seek to investigate the molecular structures of CE, their cancer-associated mutants, and their biological complexes to derive mechanistic insights into their roles in cancer. These results will also be useful for future development of novel anticancer strategies targeting at CE regulation.
Recent whole-genome and whole-exome sequencing efforts have revealed that chromatin enzymes (CE) are among the most frequently mutated gene class in both solid and hematological malignancies. CE mutations have been reportedly found in human cancers including that of kidney (Varela et al., Nature, 2011), bile duct, (Ong et al., Nature Genet, 2012) and stomach (Zang et al., Nature Genet, 2012). These mutations include loss-of-function (LOF) mutations in CE such as PBRM1, ARID1A, MLL3, SETD2, and UTX. To date, how these mutations contribute to tumorigenesis remains unknown. To address this issue, a comprehensive CE program consisting of molecular and cellular studies, synthetic lethal screening, transgenic mouse modeling, and drug testing has been in place to investigate the roles of CE in cancer. A key aspect that is currently lacking is the structural mechanisms of CE and how their mutations affect normal chromatin regulation. As an essential and complimentary part of the existing CE program, our laboratory uses bioinformatics, computational biology, x-ray crystallography and biochemical approaches to elucidate the mechanistic basis underlying how CE mutations contribute to tumorigenesis. Our results will shed light into future development of novel anticancer strategies targeting at CE regulation.
- Lim WK, Ong CK, Tan J, Thike AA, Ng CC, Rajasegaran V, Myint SS, Nagarajan S, Nasir ND, McPherson JR, Cutcutache I, Poore G, Tay ST, Ooi WS, Tan VK, Hartman M, Ong KW, Tan BK, Rozen SG, Tan PH, Tan P, Teh BT. Exome sequencing identifies highly recurrent MED12 somatic mutations in breast fibroadenoma. Nature Genet 46(8): 877–880, 2014
- Chan-on W, Nairismägi M-L, Ong CK, Dima S, Pairojkul C, Lim KH, McPherson JR, Lim WK, Cucutache I, Heng HL, Ooi L, Chung A, Chow P, Cheow PC, Lee SY, Huat ITB, Duda D, Nastase A, Myint SS, Wong BH, Gan A, Rajasegaran V, Ng CCY, Jusakul A, Zhang S, Vohra P, Yu W, Huang D, Yongvanit P, Wongkham S, Khuntikeo N, Bhudhisawasdi V, Popescu I, Rozen SG, Tan P, Teh BT. 2013. Distinct mutational patters of infection and non-infection-related bile duct cancers revealed by exome sequencing. Nature Genet. 45(12): 1474–1478
- Poon SL, Pang ST, McPherson JR, Yu W, Huang KK, Guan P, Weng WH, Siew EY, Liu Y, Heng HL, Chong SC, Gan A, Tay ST, Lim WK, Cutcutache I, Huang D, Ler LD, Nairismägi ML, Lee MH, Chang YH, Yu KJ, Chan-on W, Li BK, Yuan YF, Qiang CN, Ng KF, Wu CF, Hsu CL, Bunte RM, Stratton MR, Futureal PA, Sung WK, Chuang CK, Ong CK, Rozen SG, Tan P, Teh BT. 2013. Genome-wide mutational signatures of aristolochic acid and its application as a screening tool. Sci Transl Med 5(197): 197ra 101. 4.
- Ong CK, Subimerb C, Pairojkul C, Wongkham S, Cutcutache I, Yu W, McPherson JR, Allen GE, Ng CC, Wong BH, Myint SS, Rajasegaran V, Heng HL, Gan A, Zang ZJ, Wu Y, Wu J, Lee MH, Huang D, Ong P, Chan-on W, Cao Y, Qian CN, Lim KH, Ooi A, Dykema K, Furge K, Kukongviriyapan V, Sripa B, Wongkham C, Yongvanit P, Futreal PA, Bhudhisawasdi V, Rozen S, Tan P, Teh BT. Exome sequencing of liver fluke-associated cholangiocarcinoma. Nat Genet. 2012 May 6;44(6):690-3.
- Koo GC, Tan SY, Tang T, Poon SL, Allen GE, Tan L, Chong SC, Ong WS, Tay K, Tao M, Quek R, Loong S, Yeoh KW, Yap SP, Lee KA, Lim LC, Tan D, Goh C, Cutcutache I, Yu W, Ng CCY , Rajasegaran V, Heng HL, Gan A, Ong CK, Rozen S, Tan P, Teh BT, Lim ST. 2012. Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma. Cancer Discov 2(7): 591–597.
- Zang ZJ, Cutcutache I, Poon SL, Zhang SL, McPherson JR, Tao J, Rajasegaran V, Heng HL, Deng N, Gan A, Lim KH, Ong CK, Huang D, Chin SY, Tan IB, Ng CC, Yu W, Wu Y, Lee M, Wu J, Poh D, Wan WK, Rha SY, So J, Salto-Tellez M, Yeoh KG, Wong WK, Zhu YJ, Futreal PA, Pang B, Ruan Y, Hillmer AM, Bertrand D, Nagarajan N, Rozen S, Teh BT, Tan P. Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nat Genet. 2012 May;44(5):570-4.
- Ooi A, Wong J-C, Petillo D, Roossien D, Perrier-Trudova V, Whitten D, Hui Min BW, Tan M-H, Zhang Z, Yang XJ, Zhou M,Gardie B, Molinie V, Richard S, Tan PH, Teh BT, Furge KA. 2011. An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell 20(4): 511–523.
- Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, Davies H, Jones D, Lin ML, Teague J, Bignell G, Butler A, Cho J, Dalgliesh GL, Galappaththige D, Greenman C, Hardy C, Jia M, Latimer C, Lau KW, Marshall J, McLaren S, Menzies A, Mudie L, Stebbings L, Largaespada DA, Wessels LF, Richard S, Kahnoski RJ, Anema J, Tuveson DA, Perez-Mancera PA, Mustonen V, Fischer A, Adams DJ, Rust A, Chan-on W, Subimerb C, Dykema K, Furge K, Campbell PJ, Teh BT, Stratton MR, Futreal PA. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature. 2011 Jan 27;469(7331):539-42.
- Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, Butler A, Davies H, Edkins S, Hardy C, Latimer C, Teague J, Andrews J, Barthorpe S, Beare D, Buck G, Campbell PJ, Forbes S, Jia M, Jones D, Knott H, Kok CY, Lau KW, Leroy C, Lin ML, McBride DJ, Maddison M, Maguire S, McLay K, Menzies A, Mironenko T, Mulderrig L, Mudie L, O’Meara S, Pleasance E, Rajasingham A, Shepherd R, Smith R, Stebbings L, Stephens P, Tang G, Tarpey PS, Turrell K, Dykema KJ, Khoo SK, Petillo D, Wondergem B, Anema J, Kahnoski RJ, Teh BT, Stratton MR, Futreal PA. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature. 2010 Jan 21;463(7279):360-3.
- Van Haaften G, Dalgliesh GL, Davies H, Chen L, Bignell G, Greenman C, Edkins S, Hardy C, O’Meara S, Teague J, Butler A, Hinton J, Latimer C, Andrews J, Barthorpe S, Beare D, Buck G, Campbell PJ, Cole J, Forbes S, Jia M, Jones D, Kok CY, Leroy C, Lin ML, McBride DJ, Maddison M, Maquire S, McLay K, Menzies A, Mironenko T, Mulderrig L, Mudie L, Pleasance E, Shepherd R, Smith R, Stebbings L, Stephens P, Tang G, Tarpey PS, Turner R, Turrell K, Varian J, West S, Widaa S, Wray P, Collins VP, Ichimura K, Law S, Wong J, Yuen ST, Leung SY, Tonon G, DePinho RA, Tai YT, Anderson KC, Kahnoski RJ, Massie A, Khoo SK, Teh BT, Stratton MR, Futreal PA. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat Genet. 2009 May;41(5):521-3.
|Name||TEH Bin Tean|
|Affiliations||Senior Principal Investigator, Cancer Science Institute of Singapore, NUS
Professor, Duke-NUS Graduate Medical School
Principal Investigator, National Cancer Centre (Singapore)
|Institute||Degree (if applicable)||Year(s)|
|Karolinska Institute, Sweden||Ph.D.||1997|
|University of Queensland, Australia||M.D.||1992|
|•||Senior Principal Investigator, Cancer Science Institute of Singapore, National University of Singapore||2013 – Present|
|•||Professor, DUKE-NUS Graduate Medical School, Singapore||2009 – Present|
|•||Principal Investigator, National Cancer Centre, Singapore||2007 – Present|
|•||Group Director, Translational Research, SingHealth||2010 – 2012|
NG Ley Moy
Structural biology of chromatin enzymes.
Responsible for lab management and carrying out experiments.
|•||American Society for Clinical Investigation (ASCI)||2014|
|•||Singapore Translational Research Investigator (STaR) Award||2009|