Epigenetic regulators: multifunctional proteins modulating hypoxia-inducible factor-α protein stability and activity

Abstract

The hypoxia-inducible factor (HIF) is a heterodimeric transcription factor governing a transcriptional program in response to reduced O2 availability in metazoans. It contributes to physiology and pathogenesis of many human diseases through its downstream target genes. Emerging studies have shown that the transcriptional activity of HIF is highly regulated at multiple levels and the epigenetic regulators are essential for HIF-mediated transactivation. In this review, we will discuss the comprehensive regulation of HIF transcriptional activity by different types of epigenetic regulators.

ZMYND8 acetylation mediates HIF-dependent breast cancer progression and metastasis

“…ZMYND8 itself is a HIF-1 and HIF-2 target gene, and thus provides a positive feedback mechanism that amplifies HIFmediated transactivation and subsequent breast cancer progression and metastasis ( Figure 13). Several epigenetic regulators have been shown to coactivate a subset of HIF target genes in cancer cells (7,26,27,43). Our RNA-seq and ChIP-seq data indicate that ZMYND8 co-occupies more than 85% of the genome-wide HIF-1 binding sites and activates more than 60% of the global HIF-dependent coding genes in breast cancer cells, indicating that ZMYND8 also regulates HIF-dependent long noncoding RNAs as they are the direct HIF targets under hypoxia (37).…”

“…The histone acetyltransferases p300, CBP, and TIP60 induce acetylation of histones H3 and H4 to increase transcription of a subset of HIF-1 target genes (27,28). HDACs 1-7 are also known to enhance or suppress HIF-1 transcriptional activity via the different mechanisms (26). We have demonstrated that JMJD2C demethylates trimethyl lysine 9 of histone H3 at the HREs to increase HIF-1-mediated transactivation in human cancer cells (7).…”

“…Epigenetic regulators are essential for HIF-mediated transactivation (26). The histone acetyltransferases p300, CBP, and TIP60 induce acetylation of histones H3 and H4 to increase transcription of a subset of HIF-1 target genes (27,28).…”

Precocious neuronal differentiation and disrupted oxygen responses in Kabuki syndrome

“…Strikingly, loss of KDM5A, whose activity opposes that of KMT2D at H3K4 sites, caused upregulation of hypoxia-responsive genes (37), i.e., an effect opposite to the present KS1-associated suppression of hypoxia response genes, such as Klf10 and Bcl2/adenovirus E1B 19-KD protein-interacting protein 3-like (Bnip3l). Several histone demethylases, and at least 33 chromatin modifiers in total, have been shown to affect hypoxia response genes, 11 of these associating with developmental disorders or cancers, yet KMT2D and other histone methyltransferases have not yet been implicated (38).…”

ZMYND8 is a primary HIF coactivator that mediates breast cancer progression

“…2 Our previous studies and others have shown that epigenetic regulators, including writers and erasers, are required for HIF-mediated transactivation. 3 However, how the epigenetic reader modulates HIF transcriptional activity to promote breast tumor progression and metastasis is poorly understood.…”