title: A novel function of novobiocin: disrupting the interaction of HIF 1α and p300/CBP through direct binding to the HIF1α C-terminal activation domain.
abstract: Hypoxia-inducible factor 1α (HIF1α) is an important cellular survival protein under hypoxic conditions, regulating the cellular response to low oxygen tension via recruitment of a transcriptional co-activator, p300/CBP. p300/CBP induces expression of multiple genes involved in cell survival, proliferation, angiogenesis, and tumor development. Thus, a strategy to inhibit hypoxic responses in tumors may be to target the protein-protein interaction between HIF1α and p300/CBP. Here, we document, for the first time, that the aminocoumarin antibiotic, novobiocin, directly blocks the protein-protein interaction between the HIF1α C-terminal activation domain (CTAD) and the cysteine-histidine rich (CH1) region of p300/CBP. Also, novobiocin down-regulated HIF1α-controlled gene expression, specifically CA9, which is related to tumorigenesis. In a monolayer cell culture, novobiocin inhibited cell proliferation and colony formation in the MCF-7 human breast adenocarcinoma cell line and the A549 human lung cancer cell line. Rescue experiments revealed that the recombinant CTAD fragment of HIF1α partially reversed novobiocin's inhibitory effects on cell proliferation and colony formation in MCF-7 cells. These findings suggest a novel mechanism of action for novobiocin which has the potential for innovative therapeutic use in tumor treatment.
authors.affiliation: College of Life Science, Jilin University, Changchun, Jilin, China.
authors.forename: Donglu
authors.initials: D
authors.lastname: Wu
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Rui
authors.initials: R
authors.lastname: Zhao
authors.forename: Guang
authors.initials: G
authors.lastname: Chen
authors.forename: Yong
authors.initials: Y
authors.lastname: Cai
authors.forename: Jingji
authors.initials: J
authors.lastname: Jin
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D050881:E1A-Associated p300 Protein / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D061986:MCF-7 Cells; D009675:Novobiocin / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry / Q000302:isolation & purification; D011485:Protein Binding / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010446:Peptide Fragments; D009675:Novobiocin; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases