Congratulations to Dr Toh Tan Boon, Research Fellow from Dr Edward Chow’s group, who recently received a travel award to attend and present his research at the EMBO Workshop “Metabolic Disorders and Liver Cancer”!

This EMBO Workshop aims to provide the most important and up-to-date research in the field of liver cancer and metabolism, and was held from 23 – 26 April 2017 at Palma de Mallorca, Spain.

Dr Chow’s group studies how specific oncogenes regulate the tumorigenesis including the formation and maintenance of tumor-initiating cancer stem cells (CSCs), with a focus on hepatic cancers, which has some of the highest incidences in Asia. Dr Toh’s abstract, titled ‘Epigenetic Regulation by G9a in Myc-driven Liver Cancer’, was selected as one of the ten short talks for the workshop.

Dr Toh’s exceptional findings and outstanding presentation has won him the ‘Best Short Talk’ award at the Workshop. This award was supported by the Boehringer Ingelheim Foundation.

Epigenetic Regulation by G9a in Myc-driven Liver Cancer

Tan Boon Toh1, Jhin Jieh Lim1, Lissa Nurrul Abdullah1, Edward Kai-Hua Chow1,2
1 Cancer Science Institute of Singapore, National University of Singapore
2 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore

Liver cancer is the second most common cause of cancer-related death in the world with the highest incidence in Asia. Current treatments have limited efficacy in patients with advanced HCC, and the only clinically-approved neoplastic agent for the treatment of advanced HCC is Sorafenib, a multi-tyrosine kinase inhibitor. Despite modest survival benefits shown by Sorafenib in large randomized clinical trial studies, some patients went on to develop resistance to the therapy. Therefore, there is a need to develop better therapeutic options for the treatment of HCC. Utilizing our oncogene-specific mouse models of cancer, we have previously demonstrated that oncogenes such as Myc, determine specific cancer properties. Myc mediates a number of biological functions through epigenetic regulation, yet the mechanisms of this regulation as well as therapeutic implications in cancers are unclear. We decided to use our Myc liver tumor model to investigate the epigenetic regulation of HCC. We showed that Myc-driven liver tumors have a unique H3K9 methylation pattern with corresponding upregulation of G9a. This phenomenon of increased H3K9 methylation and G9a was further observed in our Myc-positive HCC patient-derived xenografts (PDXs), demonstrating the clinical relevance of our tumor model. In addition, using both potent and specific pharmacological inhibitors of G9a (UNC0646 and UNC0642) and genetic knockdown of G9a by lentiviral means, we were able to reduce the global H3K9me2 and Myc levels significantly, with concomitant increased in tumor suppressor genes important for metastasis. More importantly, we showed that HCC patients with higher Myc and G9a expression levels portend a poorer survival with lower mean survival months. Our work suggests that targeting G9a could prove to be a potential therapeutic avenue for Myc-driven liver cancer. This will increase our understanding of the underlying epigenetic mechanisms of aggressive tumor initiation as well.