The NUS Yong Loo Lin School of Medicine 6^th Annual Graduate Scientific Congress took place on 26^th January 2016 at NUHS Tower Block Auditorium. This is an annual gathering for graduate students to interact, share and showcase their scientific discoveries through oral and poster presentations. Congratulations to our very own CSI graduate students for doing an excellent job in this meeting and receiving multiple awards.

Deepa Rajagopalan

Supervisor: Dr Sudhakar Jha

1^st Runner-up Oral Presentation Award

TIP60 Represses TERT by Inhibiting the Function of Sp1

HIV-1 TAT interacting protein (TIP60) belongs to the MYST (Moz, Ybf2/Sas3, Sas2 and TIP60) family of acetyltransferases and is a bonafide haploinsufficient tumor suppressor. However, a mechanistic understanding of its tumor suppressor function is lacking. TIP60 expression is downregulated in different tumor types including virus-induced cancers. In Human Papilloma Virus (HPV) induced cervical cancer TIP60 down-regulates the expression of viral oncoprotein E6 and E6 destabilizes TIP60 by cooperating with a cellular ligase EDD1. This feedback loop led us to investigate the function of TIP60 during a viral infection that make it an attractive target for oncoproteins. Using molecular biology approaches such as Chromatin immunoprecipitation, cell growth assays and expression studies in HeLa cervical cancer cells, we identified TIP60 to be a repressor of TERT (human telomerase reverse transcriptase), a key driver for immortalization. In this conference, I will discuss data that establishes the regulation of the TERT promoter by TIP60, to repress telomerase expression and activity. This repression is achieved by inhibiting the binding of Sp1, a transcription factor, to the TERT promoter and is dependent on E6 expression in HeLa cells. We also identified Sp1 to be acetylated by TIP60 in vivo. Overexpression of TERT could partially rescue the growth suppression phenotype observed upon TIP60 overexpression, thus signifying the biological importance of this repression of TERT. To summarize, this study has identified a novel repressive mechanism acting at the TERT promoter in virus-induced malignancies as well as an insight into the role of TIP60 as a tumor suppressor.

 

Regina Wong Wan Ju

Supervisor: Dr Takaomi Sanda

Best Poster Presentation Award

The Role of TAL1 Complex in Transcription Activation in T-cell Acute Lymphoblastic Leukemia

Analysis of DNA binding of RNA Pol II has demonstrated that the target genes of the TAL1 complex showed significant extension of Pol II binding through the gene body compared to non TAL1-target genes. Similarly, analysis of histone status also showed that many of TAL1 targets are actively transcribed. shRNA-mediated knockdown of TAL1 resulted in a marked reduction in the phosphorylation on carboxyl-terminal domain of RNA Pol II at the serine 2 residue, a transcription elongation marker. These results suggest that the TAL1 complex promotes transcription elongation by controlling the expression of downstream targets. Our study highlights a novel role of TAL1 complex in the regulation of transcriptional activation.

 

Wang Chao

Supervisor: Dr Alan Prem Kumar

Best Poster Presentation Award

DDX20 as a Surrogate Marker for Simvastatin Response in Triple Negative Breast Cancer

Simvastatin, a lipophilic statin used for lowering cholesterol, inhibits 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the key enzyme of the mevalonate pathway. Studies have shown that cancer cells express dysregulated level of HMGCR and statins exert anti-tumoral activities. Several clinical trials have reported simvastatin and other lipophilic statin-induced anti-proliferative effects in breast cancer. DDX20 is an RNA helicase involved in many cellular processes, and our group has recently identified it as a potential oncogene, promoting proliferation and metastasis in triple negative breast cancers (TNBCs). Interest is increasing rapidly in the use of surrogate markers as primary measures of the effectiveness of investigational drugs in clinical trials. In this study, we aim to investigate if DDX20, highly expressed in TNBCs, could serve as a surrogate marker for simvastatin treatment response. A correlation between 17 genes of the mevalonate pathway and DDX20 expression was assessed in a cohort of 1325 breast cancer tumors, with result showing that HMGCR has the highest positive correlation. Our following in vitro study showed TNBC are more responsive to simvastatin treatment compared to cells of other molecular subtypes. Exposure of TNBC cells, MDA-MB-231, to simvastatin resulted in DDX20 downregulation in a Rho-dependent manner. Conversely, forced expression of DDX20 abrogated the anti-metastatic activity of simvastatin. A similar result was observed in the mouse model, where simvastatin-treated mice showed significantly fewer visible lung metastases compared to placebo group. Immunohistochemical (IHC) staining on these lung tissues showed a decrease in DDX20 expression in simvastatin-treated group, corroborating our observations in vitro.  Overall, our study suggests DDX20 is a potential surrogate marker for simvastatin treatment response in breast cancers and a long term implication of our findings is the possibility of an effective combinatorial therapeutic intervention using simvastatin (to suppress DDX20 gene expression) and a suitable first-line agent to treat invasive breast cancer.

 

Dr Chin Wai Loon, Desmond

Supervisor: A/Prof Motomi Osato

Best Graduate Research Publication Award

Mouse Models for Core Binding Factor Leukaemia

RUNX1 and CBFB are among the most frequently mutated genes in human leukemias. Genetic alterations such as chromosomal translocations, copy number variations and point mutations have been widely reported to result in the malfunction of RUNX transcription factors. Leukemias arising from such alterations in RUNX family genes are collectively termed core binding factor (CBF) leukemias. Although adult CBF leukemias generally are considered a favorable risk group as compared with other forms of acute myeloid leukemia, the 5-year survival rate remains low. An improved understanding of the molecular mechanism for CBF leukemia is imperative to uncover novel treatment options. Over the years, retroviral transduction-transplantation assays and transgenic, knockin and knockout mouse models alone or in combination with mutagenesis have been used to study the roles of RUNX alterations in leukemogenesis. Although successful in inducing leukemia, the existing assays and models possess many inherent limitations. A CBF leukemia model which induces leukemia with complete penetrance and short latency would be ideal as a platform for drug discovery. Here, we summarize the currently available mouse models which have been utilized to study CBF leukemias, discuss the advantages and limitations of individual experimental systems, and propose suggestions for improvements of mouse models.