Suppression of tumor growth through disruption of hypoxia-inducible transcription.
Chronic hypoxia, a hallmark of many tumors, is associated with angiogenesis and tumor progression. Strategies to treat tumors have been developed in which tumor cells are targeted with drugs or gene-therapy vectors specifically activated under hypoxic conditions. Here we report a different approach, in which the normal transcriptional response to hypoxia is selectively disrupted. Our data indicate that specific blockade of the interaction of hypoxia-inducible factor with the CH1 domain of its p300 and CREB binding protein transcriptional coactivators leads to attenuation of hypoxia-inducible gene expression and diminution of tumor growth. Thus, disrupting the normal co-activational response to hypoxia may be a new and useful therapeutic strategy.
Kung
A L
AL
The Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115,USA.
Wang
S
S
Klco
J M
JM
Kaelin
W G
WG
Livingston
D M
DM
D000818:Animals; D001665:Binding Sites; D050882:CREB-Binding Protein; D015687:Cell Hypoxia / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050881:E1A-Associated p300 Protein; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000628:therapy*; D009389:Neovascularization, Pathologic; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse