Anatomy and Neuroscience - Research Publications

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    BCL-XL is an actionable target for treatment of malignant pleural mesothelioma
    Arulananda, S ; O'Brien, M ; Evangelista, M ; Harris, TJ ; Steinohrt, NS ; Jenkins, LJ ; Walkiewicz, M ; O'Donoghue, RJJ ; Poh, AR ; Thapa, B ; Williams, DS ; Leong, T ; Mariadason, JM ; Li, X ; Cebon, J ; Lee, EF ; John, T ; Douglas Fairlie, W (SPRINGERNATURE, 2020-10-31)
    Despite having one of the lowest survival rates of all cancers, there have been no new approved treatments for malignant pleural mesothelioma (MPM) in over a decade. Standard-of-care treatment relies on Cisplatin plus Pemetrexed chemotherapy. Here, we tested a suite of BH3-mimetic drugs targeting BCL-2 pro-survival proteins of the intrinsic apoptotic pathway. We found BCL-XL is the dominant pro-survival protein in a panel of cell lines in vitro, though potent, synergistic cell killing occurred with MCL-1 co-targeting. This correlates with high-level expression of BCL-XL and MCL-1 in cell lines and a large cohort of patient tumour samples. BCL-XL inhibition combined with Cisplatin also enhanced cell killing. In vivo BCL-XL inhibition was as effective as Cisplatin, and the combination enhanced tumour growth control and survival. Genetic ablation of MCL-1 also enhanced the effects of BCL-XL inhibitors, in vivo. Combined, these data provide a compelling rationale for the clinical investigation of BH3-mimetics targeting BCL-XL in MPM.
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    Deletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity
    Davalos-Salas, M ; Montgomery, MK ; Reehorst, CM ; Nightingale, R ; Ng, I ; Anderton, H ; Al-Obaidi, S ; Lesmana, A ; Scott, CM ; Ioannidis, P ; Kalra, H ; Keerthikumar, S ; Togel, L ; Rigopoulos, A ; Gong, SJ ; Williams, DS ; Yoganantharaja, P ; Bell-Anderson, K ; Mathivanan, S ; Gibert, Y ; Hiebert, S ; Scott, AM ; Watt, MJ ; Mariadason, JM (NATURE PUBLISHING GROUP, 2019-11-22)
    Histone deacetylase 3 (Hdac3) regulates the expression of lipid metabolism genes in multiple tissues, however its role in regulating lipid metabolism in the intestinal epithelium is unknown. Here we demonstrate that intestine-specific deletion of Hdac3 (Hdac3IKO) protects mice from diet induced obesity. Intestinal epithelial cells (IECs) from Hdac3IKO mice display co-ordinate induction of genes and proteins involved in mitochondrial and peroxisomal β-oxidation, have an increased rate of fatty acid oxidation, and undergo marked remodelling of their lipidome, particularly a reduction in long chain triglycerides. Many HDAC3-regulated fatty oxidation genes are transcriptional targets of the PPAR family of nuclear receptors, Hdac3 deletion enhances their induction by PPAR-agonists, and pharmacological HDAC3 inhibition induces their expression in enterocytes. These findings establish a central role for HDAC3 in co-ordinating PPAR-regulated lipid oxidation in the intestinal epithelium, and identify intestinal HDAC3 as a potential therapeutic target for preventing obesity and related diseases.