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• W4310668052 endingPage "1064.e7" @default.
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• W4310668052 abstract "•HIF-1α transcriptional response can be dynamic in subpopulation of cancer cells •Lactate, a byproduct of HIF-1α-induced glycolysis, drives HIF-1α oscillations •Lactate can serve as a quorum-sensing signal to convey information about cell density •Emergent HIF-1α oscillations allow tumor to escape HIF-1α-induced cell-cycle arrest Response to hypoxia is a highly regulated process, but little is known about single-cell responses to hypoxic conditions. Using fluorescent reporters of hypoxia response factor-1α (HIF-1α) activity in various cancer cell lines and patient-derived cancer cells, we show that hypoxic responses in individual cancer cells can be highly dynamic and variable. These responses fall into three classes, including oscillatory activity. We identify a molecular mechanism that can account for all three response classes, implicating reactive-oxygen-species-dependent chaperone-mediated autophagy of HIF-1α in a subset of cells. Furthermore, we show that oscillatory response is modulated by the abundance of extracellular lactate in a quorum-sensing-like mechanism. We show that oscillatory HIF-1α activity rescues hypoxia-mediated inhibition of cell division and causes broad suppression of genes downregulated in cancers and activation of genes upregulated in many cancers, suggesting a mechanism for aggressive growth in a subset of hypoxic tumor cells. Response to hypoxia is a highly regulated process, but little is known about single-cell responses to hypoxic conditions. Using fluorescent reporters of hypoxia response factor-1α (HIF-1α) activity in various cancer cell lines and patient-derived cancer cells, we show that hypoxic responses in individual cancer cells can be highly dynamic and variable. These responses fall into three classes, including oscillatory activity. We identify a molecular mechanism that can account for all three response classes, implicating reactive-oxygen-species-dependent chaperone-mediated autophagy of HIF-1α in a subset of cells. Furthermore, we show that oscillatory response is modulated by the abundance of extracellular lactate in a quorum-sensing-like mechanism. We show that oscillatory HIF-1α activity rescues hypoxia-mediated inhibition of cell division and causes broad suppression of genes downregulated in cancers and activation of genes upregulated in many cancers, suggesting a mechanism for aggressive growth in a subset of hypoxic tumor cells." @default.
• W4310668052 created "2022-12-15" @default.
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• W4310668052 date "2022-12-01" @default.
• W4310668052 modified "2023-10-15" @default.
• W4310668052 title "Lactate-dependent chaperone-mediated autophagy induces oscillatory HIF-1α activity promoting proliferation of hypoxic cells" @default.
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• W4310668052 doi "https://doi.org/10.1016/j.cels.2022.11.003" @default.
• W4310668052 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36462504" @default.
• W4310668052 hasPublicationYear "2022" @default.
• W4310668052 type Work @default.

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