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Open Access Research article

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

Michael Boettcher1, Andrew Lawson1, Viola Ladenburger1, Johannes Fredebohm1, Jonas Wolf1, Jörg D Hoheisel1, Christian Frezza2* and Tomer Shlomi34*

Author Affiliations

1 Division of Functional Genome Analysis, Deutsches Krebsforschungszentrum, Heidelberg, Germany

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

3 Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA

4 Department of Computer Science, Technion, Haifa 32000, Israel

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BMC Genomics 2014, 15:158  doi:10.1186/1471-2164-15-158

Published: 25 February 2014

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.

Keywords:
HLRCC; Fumarate hydratase-deficiency; High-throughput RNAi screen; Adenylate cyclase