期刊
JOURNAL OF BONE AND MINERAL RESEARCH
卷 31, 期 6, 页码 1287-1299出版社
WILEY-BLACKWELL
DOI: 10.1002/jbmr.2787
关键词
INTERVERTEBRAL DISC; NUCLEUS PULPOSUS; HIF-1; HYPOXIA; HDAC6; TRANSCRIPTION FACTOR
资金
- National Institutes of Health [R01AR055655, R01AR064733, R01AR050087]
- [T32AR052273]
- [F30AR066506]
The objective of this study was to determine the role of histone deacetylases (HDACs) in regulating HIF-1 protein stability and activity in nucleus pulposus (NP) cells. Treatment of NP cells with pan-HDAC inhibitor TSA resulted in decreased HIF-1 levels under both normoxia and hypoxia in a dose-dependent fashion. TSA-mediated HIF-1 degradation was rescued by concomitant inhibition of not only the 26S proteasome but also PHD2 function. Moreover, TSA treatment of PHD2(-/-) cells had little effect on HIF-1 levels, supporting the notion that inhibition of PHD2 function by HDACs contributed to HIF-1 stabilization. Surprisingly, class-specific HDAC inhibitors did not affect HIF-1 protein stability, indicating that multiple HDACs controlled HIF-1 stability by regulating HIF-1-PHD2 interaction in NP cells. Interestingly, lower-dose TSA that did not affect HIF-1 stability decreased its activity and target gene expression. Likewise, rescue of TSA-mediated HIF-1 protein degradation by blocking proteasomal or PHD activity did not restore HIF-1 activity, suggesting that HDACs independently regulate HIF-1 stability and activity. Noteworthy, selective inhibition of HDAC6 and not of class I and IIa HDACs decreased HIF-1-mediated transcription under hypoxia to a similar extent as lower-dose TSA, contrasting the reported role of HDAC6 as a transcriptional repressor in other cell types. Moreover, HDAC6 inhibition completely blocked TSA effects on HIF-1 activity. HDAC6 associated with and deacetylated HSP90, an important cofactor for HIF-1 function in NP cells, and HDAC6 inhibition decreased p300 transactivation in NP cells. Taken together, these results suggest that although multiple class I and class IIa HDACs control HIF-1 stability, HDAC6, a class IIb HDAC, is a novel mediator of HIF-1 activity in NP cells possibly through promoting action of critical HIF-1 cofactors. (c) 2016 American Society for Bone and Mineral Research.
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