A Novel Function Of Novobiocin

Hypoxia-inducible factor1(HIF1α) is an important cellularsurvival protein under hypoxic conditions, regulating the cellularresponse to low oxygen tension via recruitment of a transcriptionalco-activator, p300/CBP. p300/CBP induces expression of multiple genesinvolved in cell survival, proliferation, angiogenesis, and tumordevelopment. Thus, a strategy to inhibit hypoxic responses in tumorsmay be to target the protein-protein interaction between HIF1α andp300/CBP. Here, we document, for the first time, that theaminocoumarin antibiotic, novobiocin, directly blocks theprotein-protein interaction between the HIF1α C-terminal activationdomain (CTAD) and the cysteine-histidine rich (CH1) region ofp300/CBP. Also, novobiocin down-regulated HIF1α-controlled geneexpression, specifically CA9, which is related to tumorigenesis. In amonolayer cell culture, novobiocin inhibited cell proliferation andcolony formation in the MCF-7human breast adenocarcinoma cell lineand the A549human lung cancer cell line. Rescue experiments revealedthat the recombinant CTAD fragment of HIF1α partially reversednovobiocin’s inhibitory effects on cell proliferation and colonyformation in MCF-7cells. These findings suggest a novel mechanism of action for novobiocin which has the potential for innovative therapeuticuse in tumor treatment.