PITX1, a specificity determinant in the HIF-1α-mediated transcriptional response to hypoxia

Sharon Mudie, Daniel Bandarra, Michael Batie, John Biddlestone, Sonia Moniz, Brian Ortmann, Alena Shmakova, Sonia Rocha

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    Abstract

    A17 Hypoxia is an important developmental cue for multicellular organisms but it is also a contributing factor for several human pathologies, such as stroke, cardiovascular diseases and cancer. In cells, hypoxia activates a major transcriptional program coordinated by the Hypoxia Inducible Factor (HIF) family. HIF can activate more than one hundred targets but not all of them are activated at the same time, and there is considerable cell type variability. In this report we identified the paired-like homeodomain pituitary transcription factor (PITX1), as a transcription factor that helps promote specificity in HIF-1α dependent target gene activation. Mechanistically, PITX1 associates with HIF-1β and it is important for the induction of certain HIF-1 dependent genes but not all. In particular, PITX1 controls the HIF-1α-dependent expression of the histone demethylases; JMJD2B, JMJD2A, JMJD2C and JMJD1B. Functionally, PITX1 is required for the survival and proliferation responses in hypoxia, as PITX1 depleted cells have higher levels of apoptotic markers and reduced proliferation. Overall, our study identified PITX1 as a key specificity factor in HIF-1α dependent responses, suggesting PITX1 as a protein to target in hypoxic cancers.

    Original languageEnglish
    Pages (from-to)3878-3891
    Number of pages14
    JournalCell Cycle
    Volume13
    Issue number24
    DOIs
    Publication statusPublished - 15 Dec 2014

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    Keywords

    • ChIP
    • HIF
    • HIF-1β
    • Histone methylation
    • Hypoxia
    • JMJC
    • JMJD2B
    • PITX1
    • Transcription

    Cite this

    Mudie, S., Bandarra, D., Batie, M., Biddlestone, J., Moniz, S., Ortmann, B., Shmakova, A., & Rocha, S. (2014). PITX1, a specificity determinant in the HIF-1α-mediated transcriptional response to hypoxia. Cell Cycle, 13(24), 3878-3891. https://doi.org/10.4161/15384101.2014.972889