Title: The unsolved mysteries of the telomere maintenance mechanism in cancer.
Summary
One striking finding in the area of cancer epigenetics has been the identification of mutated histone genes (oncohistones) in paediatric glioblastomas (pGBMs). Two H3.3 mutations are found. The first mutation replaces lysine 27 with a methionine. The second one replaces glycine 34 by an arginine (G34R). H3.3G34R mutations always overlap with ATRX and p53 mutations, and these pGBMs are activated in the Alternative Lengthening of Telomeres (ALT) telomere maintenance pathway, suggesting that H3.3G34R/ATRX/p53 mutations cooperate to drive ALT and GBM development.
We have created cell models carrying H3.3G34R/ATRX/p53 mutations to recapitulate the initial driver epigenetic events that promote ALT. KDM4 proteins are demethylases or epigenetic erasers that remove the methyl group from trimethylated H3K9 and H3K36. We find that the H3.3G34R inhibits KDM4 catalytic function of and drives its aberrant distribution. As a result, it induces aberrant histone methylation pattern and affects telomere chromatin maintenance. Our success in inducing ALT in H3.3G34R/ATRX/TP53/TERT cell model verifies the roles of H3.3 and ATRX in ALT activation and our hypothesis that ALT activation is a multi-factorial process. We propose KDM4 chromatin network as a major driver that promotes ALT pathway and the oncogenic process in GBMs. Our study provides insights into epigenetic defects linked to ATRX/H3.3 mutations and early molecular events associated with ALT.
In the H3.3G34R/ATRX mutants, we also detect DNA copy loss at ATRX-bound ribosomal DNA (rDNA) repeats, accompanied with severely reduced rRNA synthesis. ALT positive human sarcoma tumour samples are substantially reduced in rDNA copy. Moreover, ALT cancer cells show increased sensitivity to RNA polymerase I transcription inhibitor, suggesting the therapeutic potential of targeting Pol I transcription in ALT cancers. Our study provides insights into chromatin defects associated with ATRX/H3.3 mutations and development of ALT cancers.
Biography
Lee Wong did her PhD at Monash University, Australia. She worked with Prof Andy Choo at Murdoch Childrens Research Institute, Australia on centromere biology. Her centromere work had pioneered a novel concept that RNA Polymerase II dependent chromatin remodelling and noncoding RNA are key epigenetic determinants regulating centromere function and faithful chromosome segregation. In 2012, she moved to Monash University and established a new research group. The main focus of her group is to new chromatin factors important for maintaining genome stability. With this, she aims to uncover novel epigenetic mechanisms that control chromosome stability and genetic transmission, of which are pertinent to cell growth, tissue differentiation and embryo development.