Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2011:2011:197946.
doi: 10.1155/2011/197946. Epub 2010 Dec 5.

Histone deacetylase inhibitors: the epigenetic therapeutics that repress hypoxia-inducible factors

Shuyang Chen  1 , Nianli Sang
Affiliations
Review

Histone deacetylase inhibitors: the epigenetic therapeutics that repress hypoxia-inducible factors

Shuyang Chen et al. J Biomed Biotechnol. 2011.

Abstract

Histone deacetylase inhibitors (HDACIs) have been actively explored as a new generation of chemotherapeutics for cancers, generally known as epigenetic therapeutics. Recent findings indicate that several types of HDACIs repress angiogenesis, a process essential for tumor metabolism and progression. Accumulating evidence supports that this repression is mediated by disrupting the function of hypoxia-inducible factors (HIF-1, HIF-2, and collectively, HIF), which are the master regulators of angiogenesis and cellular adaptation to hypoxia. Since HIF also regulate glucose metabolism, cell survival, microenvironment remodeling, and other alterations commonly required for tumor progression, they are considered as novel targets for cancer chemotherapy. Though the precise biochemical mechanism underlying the HDACI-triggered repression of HIF function remains unclear, potential cellular factors that may link the inhibition of deacetylase activity to the repression of HIF function have been proposed. Here we review published data that inhibitors of type I/II HDACs repress HIF function by either reducing functional HIF-1α levels, or repressing HIF-α transactivation activity. In addition, underlying mechanisms and potential proteins involved in the repression will be discussed. A thorough understanding of HDACI-induced repression of HIF function may facilitate the development of future therapies to either repress or promote angiogenesis for cancer or chronic ischemic disorders, respectively.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Chemical Structures of Representative Inhibitors of Class I/II HDACs. While structurally diverse, they share one common feature: the existence of active groups targeting the zinc-dependent catalytic sites of class I/II HDACs.
Figure 2
Figure 2
Regulation of HIF-1α by Oxygen-Dependent Hydroxylation. HIF function is continuously regulated by the concentration of molecular oxygen, representing an essential part of physiological feedback loop. In this feedback loop, oxygen sensing is achieved by oxygen-dependent hydroxylation of specific amino acid residuals of HIF-α. Hydroxylation of two prolyl residuals leads to ubiquitination and proteasome-dependent degradation of HIF-α. Hydroxylation of an asparagine residual located at the CAD by FIH impairs its interaction with coactivator p300 or CBP, thus repressing the transactivation activity. Note that the hydroxylation reactions require ferrous ion and ascorbic acid as cofactors, and 2-oxoglutarate as cosubstrate.
Figure 3
Figure 3
Multiple Signaling Pathways Regulate HIF Function and Key Determinants of the Transcription Activity of HIF-1 and HIF-2. The overall function of HIF complexes is mainly determined by protein levels of the α-subunits (HIF-α) and their interactions with p300 or CBP. Multiple signaling pathways may modulate HIF function either through acting on HIF-α (stability or simple posttranslational modifications) or on p300/CBP (posttranslational modifications). Eventually, the HIF-α-p300 or HIF-α-CBP complexes serve as the integrators of these signals and coordinate the dynamic reprogramming of gene expression. HDACs may directly interact with the HIF transcription complexes, or indirectly or functionally interact with these signaling pathways and regulate HIF function.
Figure 4
Figure 4
Acetylated Proteins Potentially Involved in the Control of HIF-1α Maturation and Stability. HDACIs may lead to hyperacetylation of one or more proteins involved in the folding process of HIF-1α. Similar to HSP90 inhibition-caused blockage of normal folding and mature processes of HIF-1α, unfolded or misfolded HIF-1α remains interacting with HSP70, which may eventually trigger a ubiquitination-independent degradation process.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Schwartz DL, Bankson JA, Lemos R, Jr., et al. Radiosensitization and stromal imaging response correlates for the HIF-1 inhibitor PX-478 given with or without chemotherapy in pancreatic cancer. Molecular Cancer Therapeutics. 2010;9(7):2057–2067. - PMC - PubMed
    1. Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 2010;29(5):625–634. - PMC - PubMed
    1. Daponte A, Ioannou M, Mylonis I, et al. Prognostic significance of hypoxia-inducible factor 1 alpha(HIF-1alpha) expression in serous ovarian cancer: an immunohistochemical study. BMC Cancer. 2008;8, article no. 335 - PMC - PubMed
    1. Gómez-Raposo C, Mendiola M, Barriuso J, Casado E, Hardisson D, Redondo A. Angiogenesis and ovarian cancer. Clinical & Translational Oncology. 2009;11(9):564–571. - PubMed
    1. Jiang H, Feng Y. Hypoxia-inducible factor 1α (HIF-1α) correlated with tumor growth and apoptosis in ovarian cancer. International Journal of Gynecological Cancer. 2006;16(supplement 1):405–412. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources