High throughput synthetic lethality screen reveals a tumorigenic role of adenylate cyclase in fumarate hydratase-deficient cancer cells

Michael Boettcher, Andrew Lawson, Viola Ladenburger, Johannes Fredebohm, Jonas Wolf, Jörg D. Hoheisel, Christian Frezza, Tomer Shlomi

    Research output: Contribution to journalArticle

    9 Scopus citations

    Abstract

    Background: Synthetic lethality is an appealing technique for selectively targeting cancer cells which have acquired molecular changes that distinguish them from normal cells. High-throughput RNAi-based screens have been successfully used to identify synthetic lethal pathways with well-characterized tumor suppressors and oncogenes. The recent identification of metabolic tumor suppressors suggests that the concept of synthetic lethality can be applied to selectively target cancer metabolism as well.Results: Here, we perform a high-throughput RNAi screen to identify synthetic lethal genes with fumarate hydratase (FH), a metabolic tumor suppressor whose loss-of-function has been associated with hereditary leiomyomatosis and renal cell carcinoma (HLRCC). Our unbiased screen identified synthetic lethality between FH and several genes in heme metabolism, in accordance with recent findings. Furthermore, we identified an enrichment of synthetic lethality with adenylate cyclases. The effects were validated in an embryonic kidney cell line (HEK293T) and in HLRCC-patient derived cells (UOK262) via both genetic and pharmacological inhibition. The reliance on adenylate cyclases in FH-deficient cells is consistent with increased cyclic-AMP levels, which may act to regulate cellular energy metabolism.Conclusions: The identified synthetic lethality of FH with adenylate cyclases suggests a new potential target for treating HLRCC patients.

    Original languageEnglish (US)
    Article number158
    JournalBMC genomics
    Volume15
    Issue number1
    DOIs
    StatePublished - Feb 25 2014

    Keywords

    • Adenylate cyclase
    • Fumarate hydratase-deficiency
    • HLRCC
    • High-throughput RNAi screen

    ASJC Scopus subject areas

    • Biotechnology
    • Genetics

    Fingerprint Dive into the research topics of 'High throughput synthetic lethality screen reveals a tumorigenic role of adenylate cyclase in fumarate hydratase-deficient cancer cells'. Together they form a unique fingerprint.

  • Cite this

    Boettcher, M., Lawson, A., Ladenburger, V., Fredebohm, J., Wolf, J., Hoheisel, J. D., Frezza, C., & Shlomi, T. (2014). High throughput synthetic lethality screen reveals a tumorigenic role of adenylate cyclase in fumarate hydratase-deficient cancer cells. BMC genomics, 15(1), [158]. https://doi.org/10.1186/1471-2164-15-158