A genetic screen identifies PITX1 as a suppressor of RAS activity and tumorigenicity.
Activating mutations of RAS frequently occur in subsets of human cancers, indicating that RAS activation is important for tumorigenesis. However, a large proportion of these cancers still retain wild-type RAS alleles, suggesting that either the RAS pathway is activated in a distinct manner or another pathway is deregulated. To uncover novel tumor-suppressor genes, we screened an RNA-interference library for knockdown constructs that transform human primary cells in the absence of ectopically introduced oncogenic RAS. Here we report the identification of PITX1, whose inhibition induces the RAS pathway and tumorigenicity. Interestingly, we observed low expression of PITX1 in prostate and bladder tumors and in colon cancer cell lines containing wild-type RAS. Restoration of PITX1 in the colon cancer cells inhibited tumorigenicity in a wild-type RAS-dependent manner. Finally, we identified RASAL1, a RAS-GTPase-activating protein, as a transcription target through which PITX1 affects RAS function. Thus, PITX1 suppresses tumorigenicity by downregulating the RAS pathway through RASAL1.
Kolfschoten
Ingrid G M
IG
Division of Tumor Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
van Leeuwen
Bart
B
Berns
Katrien
K
Mullenders
Jasper
J
Beijersbergen
Roderick L
RL
Bernards
Rene
R
Voorhoeve
P Mathijs
PM
Agami
Reuven
R
D000818:Animals; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D020690:GTPase-Activating Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D015723:Gene Library; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D005820:Genetic Testing / Q000379:methods*; D005822:Genetic Vectors / Q000494:pharmacology; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000187:drug effects / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D051761:Paired Box Transcription Factors; D010641:Phenotype; D034622:RNA Interference / Q000502:physiology; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000494:pharmacology*; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology
D020690:GTPase-Activating Proteins; D018398:Homeodomain Proteins; D051761:Paired Box Transcription Factors; C580923:RASAL1 protein, human; D014157:Transcription Factors; C101485:homeobox protein PITX1; D018631:ras Proteins