Dr Jing TANDr Luyu XIELiang Kai KOHCedric NGZhimei LEEVikneswari RAJASEGARANHong Lee HENGWei LIUShane GOHJing Yi LEEAbner LIM
We have characterised the genomic landscapes of several Asian-prevalent tumour types, such as upper urinary tract urothelial cancer in Taiwan, cholangiocarcinoma in the north-east of Thailand, and NK/T-cell lymphoma and fibroepithelial tumours of the breast. Interestingly, many of the novel mutations identified involve chromatin enzymes, and this prompted us to examine how they perturb chromatin biology and the epigenome in tumorigenesis. Using epigenomic tools, such as chip-sequencing, RNA-sequencing, and methylation profiling, we have studied patient-derived cell lines and primary tumours. We are studying their epigenetic landscapes, including DNA and histone modifications, and identifying promoters, enhancers, and super-enhancers related to these mutations. In particular, we are studying the master regulators associated with super-enhancers, especially their roles in tumorigenesis. As an example, we recently profiled the super-enhancers associated with VHL mutations in clear cell renal cell carcinoma and demonstrated the tumorigenic role of a novel master regulator, ZNF395 (Figures 1 & 2 below, Yao et al., Cancer Discov. 2017). We continue to work closely with clinicians, including oncologists, surgeons, and pathologists, to understand the clinical implications of our findings, particularly how the genomic and epi-genomic landscapes of these genes correlate with various clinicopathological parameters. Finally, we collaborate with pharmaceutical and biotechnology companies to work on novel epigenetic therapeutic targets in these cancer types.
Figure 1. H3K27ac ChIP-seq shows an active ZNF395 super-enhancer only in clear cell renal cell carcinoma cells (A-498 and 786-O, bottom rows) but not normal kidney cells (PCS-400, HK2, top rows). Yao et al. 2017.
Figure 2. ZNF395 inhibition by shRNA leads to total elimination of A-498 tumours in vivo and delayed 786-O tumour growth. NC (negative control): n = 7; shZNF395-1: n = 7; shZNF395-2: n = 6. Yao et al. 2017.
1. Yao X, Tan J, Lim KJ, et al. VHL deficiency drives enhancer activation of oncogenes in clear cell renal cell carcinoma. Cancer Discov. 2017;7:1284–1305.
2. Jusakul A, Cucutache I, Yong CH, et al. Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma. Cancer Discov. 2017:7:1116–1135.
3. Ler LD, Ghosh S, Chai X, et al. Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2. Sci Transl Med. 2017;9:pii:eaai8312.
4. Fukawa T, Yan-Jiang BC, Min-Wen JC, et al. Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia. Nat Med. 2016;22:666–671.
5. Tan J, Ong CK, Lim WK, et al. Genomic landscapes of breast fibroepithelialtumors. Nat Genet. 2015;47:1341–1345.
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