DLC1 is a chromosome 8p tumor suppressor whose loss promotes hepatocellular carcinoma
- Wen Xue1,
- Alexander Krasnitz1,
- Robert Lucito1,
- Raffaella Sordella1,
- Linda VanAelst1,
- Carlos Cordon-Cardo2,
- Stephan Singer3,
- Florian Kuehnel4,
- Michael Wigler1,
- Scott Powers1,
- Lars Zender1,6, and
- Scott W. Lowe1,5,7
- 1 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
- 2 Columbia University Medical Center, New York 10032, USA;
- 3 Institute of Pathology, University Hospital, Heidelberg 69120, Germany;
- 4 Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover 30625, Germany;
- 5 Howard Hughes Medical Institute, Cold Spring Harbor, NY 11724, USA
Abstract
Deletions on chromosome 8p are common in human tumors, suggesting that one or more tumor suppressor genes reside in this region. Deleted in Liver Cancer 1 (DLC1) encodes a Rho-GTPase activating protein and is a candidate 8p tumor suppressor. We show that DLC1 knockdown cooperates with Myc to promote hepatocellular carcinoma in mice, and that reintroduction of wild-type DLC1 into hepatoma cells with low DLC1 levels suppresses tumor growth in situ. Cells with reduced DLC1 protein contain increased GTP-bound RhoA, and enforced expression a constitutively activated RhoA allele mimics DLC1 loss in promoting hepatocellular carcinogenesis. Conversely, down-regulation of RhoA selectively inhibits tumor growth of hepatoma cells with disabled DLC1. Our data validate DLC1 as a potent tumor suppressor gene and suggest that its loss creates a dependence on the RhoA pathway that may be targeted therapeutically.
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Footnotes
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↵6 Present address: Helmholtz Centre for Infection Research, Braunschweig 38124, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover 30625, Germany.
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↵7 Corresponding author.
↵7 E-MAIL lowe{at}cshl.edu; FAX (516) 367-8454.
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Supplemental material is available at http://www.genesdev.org.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1672608.
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- Received March 11, 2008.
- Accepted April 14, 2008.
- Copyright © 2008, Cold Spring Harbor Laboratory Press
