Class I and IIa HDACs Mediate HIF-1α Stability Through PHD2-Dependent Mechanism, While HDAC6, a Class IIb Member, Promotes HIF-1α Transcriptional Activity in Nucleus Pulposus Cells of the Intervertebral Disc

Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research
Zachary R SchoepflinMakarand V Risbud

Abstract

The objective of this study was to determine the role of histone deacetylases (HDACs) in regulating HIF-1α protein stability and activity in nucleus pulposus (NP) cells. Treatment of NP cells with pan-HDAC inhibitor TSA resulted in decreased HIF-1α levels under both normoxia and hypoxia in a dose-dependent fashion. TSA-mediated HIF-1α 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-1α levels, supporting the notion that inhibition of PHD2 function by HDACs contributed to HIF-1α stabilization. Surprisingly, class-specific HDAC inhibitors did not affect HIF-1α protein stability, indicating that multiple HDACs controlled HIF-1α stability by regulating HIF-1α-PHD2 interaction in NP cells. Interestingly, lower-dose TSA that did not affect HIF-1α stability decreased its activity and target gene expression. Likewise, rescue of TSA-mediated HIF-1α protein degradation by blocking proteasomal or PHD activity did not restore HIF-1 activity, suggesting that HDACs independently regulate HIF-1α stability and activity. Noteworthy, selective inhibition of HDAC6 and not of class I and IIa HDACs decreased HIF-1-mediated tra...Continue Reading

References

Nov 12, 1996·Proceedings of the National Academy of Sciences of the United States of America·Z AranyD M Livingston
May 9, 1998·Proceedings of the National Academy of Sciences of the United States of America·C A HassigS L Schreiber
Jun 22, 2000·Proceedings of the National Academy of Sciences of the United States of America·Y D WenE Seto
Feb 2, 2002·Science·David LandoMurray L Whitelaw
Apr 18, 2002·Proceedings of the National Academy of Sciences of the United States of America·Steven J FreedmanMichael J Eck
Dec 24, 2005·Proceedings of the National Academy of Sciences of the United States of America·Michal SafranWilliam G Kaelin
Jan 10, 2009·Science·Bo Chen, Constance L Cepko
Apr 7, 2009·Biochemical and Biophysical Research Communications·Younho HanKwang-Youl Lee
Sep 2, 2009·Molecular and Cellular Biology·Yoji Andrew MinamishimaWilliam G Kaelin
Feb 6, 2010·The American Journal of Pathology·Makarand V RisbudIrving M Shapiro
Sep 16, 2011·The Journal of Biological Chemistry·Hao GengDavid Z Qian
Oct 12, 2011·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Nobuyuki FujitaMakarand V Risbud
Feb 11, 2012·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Shilpa S GogateMakarand V Risbud
May 9, 2012·The EMBO Journal·Samantha N GreerMichael Ohh
Jan 7, 2014·Molecular Biology Reports·Feng-qiang YangXi Li
May 29, 2014·The Journal of Biological Chemistry·Yuichiro HiroseMakarand V Risbud
Aug 31, 2014·Matrix Biology : Journal of the International Society for Matrix Biology·Zariel I JohnsonMakarand V Risbud
Nov 21, 2014·Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society·Makarand V RisbudJudith A Hoyland

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Citations

Aug 25, 2016·BioMed Research International·Elizabeth E HullKathryn J Leyva
Jan 25, 2017·Cell Stress & Chaperones·Hyun-Wook RyuSo Hee Kwon
Dec 14, 2018·International Journal of Molecular Sciences·Maria MrakovcicLeopold F Fröhlich
Sep 25, 2017·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Elizabeth S SilagiMakarand V Risbud
May 30, 2019·International Journal of Molecular Sciences·Sabrina EhnertAndreas K Nussler
May 18, 2019·International Journal of Molecular Sciences·Maria MrakovcicLeopold F Fröhlich
May 13, 2017·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Zachary R SchoepflinMakarand V Risbud
Apr 4, 2020·Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society·Tomonori ItsujiToshikazu Kubo
Jan 8, 2020·Cancers·Maria Mrakovcic, Leopold F Fröhlich
Jun 26, 2020·Frontiers in Neurology·Martín BusteloAntonio W Danilo Gavilanes
Jan 7, 2021·Cancers·Marek SamecPeter Kubatka
Apr 24, 2021·Expert Review of Clinical Immunology·Antreas PavlidisEvangelia Papadavid
May 9, 2021·The Journal of Pharmacy and Pharmacology·Fan LiuZheng Ji
Jun 5, 2021·Nature Reviews. Rheumatology·Elizabeth S SilagiMakarand V Risbud
Apr 5, 2019·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Zhixiong MeiNi Deng
Aug 17, 2021·Frontiers in Oncology·Rihan HaiGang Yin

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