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A KLF6-driven transcriptional network links lipid homeostasis and tumour growth in renal carcinoma.

Abstract

Transcriptional networks are critical for the establishment of tissue-specific cellular states in health and disease, including cancer. Yet, the transcriptional circuits that control carcinogenesis remain poorly understood. Here we report that Kruppel like factor 6 (KLF6), a transcription factor of the zinc finger family, regulates lipid homeostasis in clear cell renal cell carcinoma (ccRCC). We show that KLF6 supports the expression of lipid metabolism genes and promotes the expression of PDGFB, which activates mTOR signalling and the downstream lipid metabolism regulators SREBF1 and SREBF2. KLF6 expression is driven by a robust super enhancer that integrates signals from multiple pathways, including the ccRCC-initiating VHL-HIF2A pathway. These results suggest an underlying mechanism for high mTOR activity in ccRCC cells. More generally, the link between super enhancer-driven transcriptional networks and essential metabolic pathways may provide clues to the mechanisms that maintain the stability of cell identity-defining transcriptional programmes in cancer.

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    MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK. UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Kuala Lumpur, 56000, Malaysia.

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    MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK.

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    MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK.

    ,

    MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK.

    ,

    MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK.

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    Academic Urology Group, Department of Surgery, University of Cambridge, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.

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    Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK.

    ,

    Academic Urology Group, Department of Surgery, University of Cambridge, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.

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    Department of Oncology, University of Cambridge, Cambridge, CB2 0XZ, UK. Department of Oncology, Addenbrooke's Hospital, Cambridge University Health Partners, Cambridge, CB2 0QQ, UK. Oncology Early Clinical Development, AstraZeneca, Cambridge, SG8 6EH, UK.

    ,

    MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK.

    ,

    MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK.

    MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK. sv358@mrc-cu.cam.ac.uk.

    Source

    Nature communications 10:1 2019 03 11 pg 1152

    MeSH

    Animals
    Carcinogenesis
    Carcinoma, Renal Cell
    Cell Line, Tumor
    Cell Proliferation
    Enhancer Elements, Genetic
    Gene Expression Profiling
    Gene Expression Regulation, Neoplastic
    Gene Regulatory Networks
    HEK293 Cells
    Humans
    Kidney
    Kidney Neoplasms
    Kruppel-Like Factor 6
    Lipid Metabolism
    Male
    Mice
    Mice, Inbred NOD
    Mice, Nude
    Mice, SCID
    Proto-Oncogene Proteins c-sis
    Signal Transduction
    Sterol Regulatory Element Binding Protein 1
    Sterol Regulatory Element Binding Protein 2
    TOR Serine-Threonine Kinases
    Xenograft Model Antitumor Assays

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    30858363

    Citation

    Syafruddin, Saiful E., et al. "A KLF6-driven Transcriptional Network Links Lipid Homeostasis and Tumour Growth in Renal Carcinoma." Nature Communications, vol. 10, no. 1, 2019, p. 1152.
    Syafruddin SE, Rodrigues P, Vojtasova E, et al. A KLF6-driven transcriptional network links lipid homeostasis and tumour growth in renal carcinoma. Nat Commun. 2019;10(1):1152.
    Syafruddin, S. E., Rodrigues, P., Vojtasova, E., Patel, S. A., Zaini, M. N., Burge, J., ... Vanharanta, S. (2019). A KLF6-driven transcriptional network links lipid homeostasis and tumour growth in renal carcinoma. Nature Communications, 10(1), p. 1152. doi:10.1038/s41467-019-09116-x.
    Syafruddin SE, et al. A KLF6-driven Transcriptional Network Links Lipid Homeostasis and Tumour Growth in Renal Carcinoma. Nat Commun. 2019 03 11;10(1):1152. PubMed PMID: 30858363.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - A KLF6-driven transcriptional network links lipid homeostasis and tumour growth in renal carcinoma. AU - Syafruddin,Saiful E, AU - Rodrigues,Paulo, AU - Vojtasova,Erika, AU - Patel,Saroor A, AU - Zaini,M Nazhif, AU - Burge,Johanna, AU - Warren,Anne Y, AU - Stewart,Grant D, AU - Eisen,Tim, AU - Bihary,Dóra, AU - Samarajiwa,Shamith A, AU - Vanharanta,Sakari, Y1 - 2019/03/11/ PY - 2018/06/29/received PY - 2019/02/15/accepted PY - 2019/3/13/entrez PY - 2019/3/13/pubmed PY - 2019/4/6/medline SP - 1152 EP - 1152 JF - Nature communications JO - Nat Commun VL - 10 IS - 1 N2 - Transcriptional networks are critical for the establishment of tissue-specific cellular states in health and disease, including cancer. Yet, the transcriptional circuits that control carcinogenesis remain poorly understood. Here we report that Kruppel like factor 6 (KLF6), a transcription factor of the zinc finger family, regulates lipid homeostasis in clear cell renal cell carcinoma (ccRCC). We show that KLF6 supports the expression of lipid metabolism genes and promotes the expression of PDGFB, which activates mTOR signalling and the downstream lipid metabolism regulators SREBF1 and SREBF2. KLF6 expression is driven by a robust super enhancer that integrates signals from multiple pathways, including the ccRCC-initiating VHL-HIF2A pathway. These results suggest an underlying mechanism for high mTOR activity in ccRCC cells. More generally, the link between super enhancer-driven transcriptional networks and essential metabolic pathways may provide clues to the mechanisms that maintain the stability of cell identity-defining transcriptional programmes in cancer. SN - 2041-1723 UR - https://www.unboundmedicine.com/medline/citation/30858363/A_KLF6-driven_transcriptional_network_links_lipid_homeostasis_and_tumour_growth_in_renal_carcinoma L2 - http://dx.doi.org/10.1038/s41467-019-09116-x DB - PRIME DP - Unbound Medicine ER -