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

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  • Saiful E. Syafruddin

    (MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre
    UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Jalan Yaacob Latiff)

  • Paulo Rodrigues

    (MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre)

  • Erika Vojtasova

    (MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre)

  • Saroor A. Patel

    (MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre)

  • M. Nazhif Zaini

    (MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre)

  • Johanna Burge

    (University of Cambridge, Addenbrooke’s Hospital, Cambridge Biomedical Campus)

  • Anne Y. Warren

    (Cambridge University Hospitals NHS Foundation Trust)

  • Grant D. Stewart

    (University of Cambridge, Addenbrooke’s Hospital, Cambridge Biomedical Campus)

  • Tim Eisen

    (University of Cambridge
    Cambridge University Health Partners
    Oncology Early Clinical Development, AstraZeneca)

  • Dóra Bihary

    (MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre)

  • Shamith A. Samarajiwa

    (MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre)

  • Sakari Vanharanta

    (MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre)

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.

Suggested Citation

  • Saiful E. Syafruddin & Paulo Rodrigues & Erika Vojtasova & Saroor A. Patel & M. Nazhif Zaini & Johanna Burge & Anne Y. Warren & Grant D. Stewart & Tim Eisen & Dóra Bihary & Shamith A. Samarajiwa & Sak, 2019. "A KLF6-driven transcriptional network links lipid homeostasis and tumour growth in renal carcinoma," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09116-x
    DOI: 10.1038/s41467-019-09116-x
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