The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.
HDAC4 Protein Regulates HIF1α Protein Lysine Acetylation and Cancer Cell Response to Hypoxia
Open accessAbstract
Hypoxia-inducible factor 1 α (HIF1α) is an essential part of the HIF-1 transcriptional complex that regulates angiogenesis, cellular metabolism, and cancer development. In von Hippel-Lindau (VHL)-null kidney cancer cell lines, we reported previously that HIF1α proteins can be acetylated and inhibited by histone deacetylase (HDAC) inhibitors or specific siRNA against HDAC4. To investigate the mechanism and biological consequence of the inhibition, we have generated stable HDAC4 knockdown via shRNA in VHL-positive normal and cancer cell lines. We report that HDAC4 regulates HIF1α protein acetylation and stability. Specifically, the HIF1α protein acetylation can be increased by HDAC4 shRNA and decreased by HDAC4 overexpression. HDAC4 shRNA inhibits HIF1α protein stability. In contrast, HDAC1 or HDAC3 shRNA has no such inhibitory effect. Mutations of the first five lysine residues (lysine 10, 11, 12, 19, and 21) to arginine within the HIF1α N terminus reduce protein acetylation but render the mutant HIF1α protein resistant to HDAC4 and HDACi-mediated inhibition. Functionally, in VHL-positive cancer cell lines, stable inhibition of HDAC4 decreases both the HIF-1 transcriptional activity and a subset of HIF-1 hypoxia target gene expression. On the cellular level, HDAC4 inhibition reduces the hypoxia-related increase of glycolysis and resistance to docetaxel chemotherapy. Taken together, the novel biological relationship between HDAC4 and HIF1α presented here suggests a potential role for the deacetylase enzyme in regulating HIF-1 cancer cell response to hypoxia and presents a more specific molecular target of inhibition.
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Cites
Targeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717
The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
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Acetylation and deacetylation of non-histone proteins
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Dimerization, DNA Binding, and Transactivation Properties of Hypoxia-inducible Factor 1
Jiang, B.-H., Rue, E., Wang, G. L., Roe, R., & Semenza, G. L. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.30.17771 · Cited by 1,106
Sirtuin 1 Modulates Cellular Responses to Hypoxia by Deacetylating Hypoxia-Inducible Factor 1α
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Regulation and Destabilization of HIF-1α by ARD1-Mediated Acetylation
Jeong, J.-W., Bae, M.-K., Ahn, M.-Y., Kim, S.-H., Sohn, T.-K., Bae, M.-H., Yoo, M.-A., Song, E. J., Lee, K.-J., & Kim, K.-W. (2002) · Cell · doi:10.1016/s0092-8674(02)01085-1 · Cited by 716
Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1α-degradative pathway
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Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth
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Self-citationRegulation of cancer cell metabolism by hypoxia-inducible factor 1
Semenza, G. L. (2009) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2008.11.009 · Cited by 469
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Cited by
Gomes, A. P., Price, N. L., Ling, A. J. Y., Moslehi, J. J., Montgomery, M. K., Rajman, L., White, J. P., Teodoro, J. S., Wrann, C. D., Hubbard, B. P., et al. (2013) · Cell · doi:10.1016/j.cell.2013.11.037 · Cited by 1,482
Single-Cell Exome Sequencing Reveals Single-Nucleotide Mutation Characteristics of a Kidney Tumor
Xu, X., Hou, Y., Yin, X., Bao, L., Tang, A., Song, L., Li, F., Tsang, S., Wu, K., Wu, H., et al. (2012) · Cell · doi:10.1016/j.cell.2012.02.025 · Cited by 667
Korbecki, J., Simińska, D., Gąssowska-Dobrowolska, M., Listos, J., Gutowska, I., Chlubek, D., & Baranowska-Bosiacka, I. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221910701 · Cited by 380
Lysine acetyltransferases and lysine deacetylases as targets for cardiovascular disease
Li, P., Ge, J., & Li, H. (2020) · Nature Reviews Cardiology · doi:10.1038/s41569-019-0235-9 · Cited by 269
HDAC4: Mechanism of Regulation and Biological Functions
Wang, Z., Qin, G., & Zhao, T. C. (2014) · Epigenomics · doi:10.2217/epi.13.73 · Cited by 239
Metadata
- Authors
- Geng, H., Harvey, C. T., Pittsenbarger, J., Liu, Q., Beer, T. M., Xue, C., & Qian, D. Z.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-11
- Volume
- 286
- Issue
- 44
- Pages
- 38095-38102
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2094206434
- Cited by
- 197
- References
- 10
- FWCI
- 3.83
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Geng, H., Harvey, C. T., Pittsenbarger, J., Liu, Q., Beer, T. M., Xue, C., & Qian, D. Z. (2011). HDAC4 Protein Regulates HIF1α Protein Lysine Acetylation and Cancer Cell Response to Hypoxia. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m111.257055
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