Altered gene transcription is a major cause of cancer. One of the main ways that cancer cells alter gene transcription is to chemically modify cell proteins called histones. This acts to ‘switch off’ the transcription of genes that help suppress tumour initiation and progression, and to ‘switch on’ the transcription of genes that induce these processes. This group is focused on understanding altered gene transcription in cancer with a view to improving anti-cancer therapies.
A/Prof Tao Liu
Myc oncoproteins including N-Myc and c-Myc are over-expressed in approximately 50 per cent of tumour tissues from the general population of cancer patients. As transcription factors, Myc oncoproteins induce tumour initiation and stimulate tumour progression by modulating gene transcription.
Recruitment of histone deacetylases (HDACs) to gene promoters leads to histone hypo-acetylation and consequent transcriptional repression, particularly of tumour suppressor genes. HDACs can be grouped into classes I, II, III and IV. Inhibitors of class I, II and IV HDACs activate the transcription of tumour suppressor genes, induce cancer cell growth arrest and programmed cell death, and have shown promising anticancer effects in patients with cancers of various organ origins. Distinct from class I, II and IV HDACs, the class III HDACs, the sirtuins (SIRTs), do not respond to the classic HDAC inhibitors currently under clinical trials.
Histone deacetylases in Myc oncogenesis
In the past five years, we have identified novel interplays among HDAC1, HDAC2, SIRT1 and Myc oncoproteins. We have shown that Myc oncoproteins block tumour cell differentiation by recruiting HDAC1 to the promoter of the tissue transglutaminase gene, leading to transcriptional repression of tissue transglutaminase, and that Myc oncoproteins stimulate cancer cell growth by inducing HDAC2 and SIRT1 gene expression.
Importantly, we have demonstrated that Myc oncoproteins form a transcriptional repressor complex with HDAC2 to block the transcription of cyclin E2, leading to cell proliferation, and form a transcriptional repressor complex with SIRT1 to block the transcription of mitogen-activated protein kinase phosphotase 3, leading to stabilisation of Myc oncoproteins.
Histone deacetylase inhibitors in cancer therapy
The Histone Modification Group has been searching for the best combination therapy with inhibitors of the class I, II and IV HDACs and other promising anticancer agents. Moreover, we have been testing the anticancer efficacy of novel inhibitors of the class III HDACs, the SIRTs, in animal models of neuroblastoma and pancreatic cancer.
We have shown that treatment of neuroblastoma tumours with SIRT inhibitors partly blocks tumour progression.
A/Prof Tao Liu
One of the most important advances in cancer research in the past five years is the identification of histone demethylases as the critical players in gene transcription, tumour initiation and progression.
In collaboration with researchers at University of North Carolina (USA) and Nagoya City University (Japan), we are currently investigating histone demethylases in modulating gene transcription, tumour initiation and progression, and investigating histone demethylase inhibitors as novel anticancer agents.
A/Prof Tao Liu
Myc oncoproteins including N-Myc and c-Myc are over-expressed in approximately 50 per cent of tumour tissues from the general population of cancer patients. One of the most important aspects of Myc oncogenesis is the stabilization/degradation of Myc oncoproteins. In the past two years, we have identified two novel pathways through which Myc oncoproteins are stabilised/degraded. We believe that the novel pathways for Myc oncoprotein stabilisation/degradation provide novel targets for cancer therapy, and are currently investigating proteins critical for the novel pathways and their roles as novel anticancer targets.
Group LeaderAssociate Professor Tao Liu
Dr Andrew Tee
Dr Pei Yan Liu
Dr Matthew Wong