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Huntington disease protein accelerates tumour development and metastasis

ABSTRACT: Huntington disease is a severe neurological disorder caused by an abnormal polyglutamine expansion in the N-terminal of the huntingtin protein. Here we show that breast tumours appear earlier when mutant huntingtin is expressed in an activated polyomavirus middle T antigen (PyVT) mouse breast cancer model as compared to the control mice expressing wild-type huntingtin. Tumours bearing mutant huntingtin have a modified gene expression pattern revealing increases in the IGF-1/Akt signalling, epithelial-mesenchymal transition and metastatic properties. Indeed, polyQ-huntingtin expressing tumours show hyper-activation of Akt pathway. Also, when mutant huntingtin is expressed, cancer cells in culture change morphology and the levels of cell adhesion and mesenchymal markers are affected in primary tumour or corresponding derived cells. As a consequence, PyVT induced lung metastasis is higher in Huntington disease mice than in the control mice. Finally, analysis of cases of Huntington disease patients developing breast cancer may suggest an increased aggressiveness of breast cancer when compared to the control population.

ORGANISM(S): Mus musculus

PROVIDER: GSE28685 | GEO | 2014/04/14

SECONDARY ACCESSION(S): PRJNA138947

REPOSITORIES: GEO

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Project description:Huntington Disease (HD) is a dominantly inherited, relentlessly progressive neurodegenerative disease. Caused by a polyglutamine expansion in the mutant huntingtin protein (mhtt), HD pathogenesis impairs function in the cerebral cortex and in medium spiny neurons of the striatum and involves transcriptional dysregulation of a number of genes. Of these genes, silencing of genes related to mitochondrial function is believed to explain metabolic dysfunction in rodent models of HD. Here we show that transglutaminase 2 (TG2), which is upregulated in HD, exacerbates transcriptional dysregulation by acting as a selective corepressor of nuclear genes. TG2 inhibition by RNA knockdown, genetic deletion, or administration of a novel irreversible, peptide-based TG2 inhibitor (ZDON) de-repressed two established regulators of mitochondrial function, PGC-1? and cytochrome c in a cell model of HD. TG2 must localize to non-coding or coding regions of these mitochondrial metabolic genes to silence their transcription. As expected, TG2 inhibition reversed the increased susceptibility of HD mouse cells and human HD myoblasts to the mitochondrial toxin, 3-nitroproprionic acid (3-NP); however, protection mediated by TG2 inhibition was not associated with improved mitochondrial bioenergetics. Indeed, an unbiased array analysis indicated that TG2 inhibition leads to normalization of not only mitochondrial genes but of nearly 40% of genes that are dysregulated in HD mouse striatal neurons, including chaperone and histone genes. Indeed, TG2 interacts directly with Histone 3 in the nucleus. Moreover, TG2 inhibition significantly attenuated photoreceptor degeneration in a Drosophila model of HD and protected mouse HD striatal neurons (YAC128) from NMDA- induced toxicity. Altogether these findings demonstrate that TG2 mediates its deleterious effects in HD by contributing to broad transcriptional dysregulation of genes representing many cellular functions. These studies define a novel HDAC-independent epigenetic strategy for treating neurodegeneration. To evaluate the effect of TG2 inhibition (treatment with ZDON, Boc-DON, CystamineA, and Control) in striatal cell lines from a transgenic model of Huntington disease (Q111) vs. control (Q7). One sample (WT.boc.3, 4068264015_G) failed the QC test and was excluded from further analyses.

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Huntington disease protein accelerates tumour development and metastasis

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