DLC1 is a chromosome 8p tumor suppressor whose loss promotes hepatocellular carcinoma.
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.
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Wen
W
Xue
Alexander
A
Krasnitz
Robert
R
Lucito
Raffaella
R
Sordella
Linda
L
Vanaelst
Carlos
C
Cordon-Cardo
Stephan
S
Singer
Florian
F
Kuehnel
Michael
M
Wigler
Scott
S
Powers
Lars
L
Zender
Scott W
SW
Lowe
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8; D016147:Genes, Tumor Suppressor; D016259:Genes, myc; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000235:genetics*; D051379:Mice; D023421:Models, Animal; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D020742:rhoA GTP-Binding Protein