The Histone Deacetylase Inhibitor, Vorinostat, Represses Hypoxia Inducible Factor 1 Alpha Expression through Translational Inhibition
Open accessAbstract
Hypoxia inducible factor 1α (HIF-1α) is a master regulator of tumor angiogenesis being one of the major targets for cancer therapy. Previous studies have shown that Histone Deacetylase Inhibitors (HDACi) block tumor angiogenesis through the inhibition of HIF-1α expression. As such, Vorinostat (Suberoylanilide Hydroxamic Acid/SAHA) and Romidepsin, two HDACis, were recently approved by the Food and Drug Administration (FDA) for the treatment of cutaneous T cell lymphoma. Although HDACis have been shown to affect HIF-1α expression by modulating its interactions with the Hsp70/Hsp90 chaperone axis or its acetylation status, the molecular mechanisms by which HDACis inhibit HIF-1α expression need to be further characterized. Here, we report that the FDA-approved HDACi Vorinostat/SAHA inhibits HIF-1α expression in liver cancer-derived cell lines, by a new mechanism independent of p53, prolyl-hydroxylases, autophagy and proteasome degradation. We found that SAHA or silencing of HDAC9 mechanism of action is due to inhibition of HIF-1α translation, which in turn, is mediated by the eukaryotic translation initiation factor--eIF3G. We also highlighted that HIF-1α translation is dramatically inhibited when SAHA is combined with eIF3H silencing. Taken together, we show that HDAC activity regulates HIF-1α translation, with HDACis such as SAHA representing a potential novel approach for the treatment of hepatocellular carcinoma.
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Vorinostat inhibits HIF-1α translation, impairs nuclear accumulation, and promotes ubiquitination-dependent proteasomal degradation, collectively suppressing HIF-1 transcriptional activity under hypoxia.
“Mechanistically, vorinostat acts at multiple regulatory levels: it inhibits HIF-1α translation, impairs nuclear accumulation, and promotes ubiquitination-dependent proteasomal degradation, collectively suppressing HIF-1 transcriptional activity under hypoxia [351,352].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [351]
The Abstract and Discussion report that vorinostat (SAHA) inhibits HIF-1α translation, and the Results show reduced HIF-1α protein levels with hypoxia-mimicking treatments. The Results section “SAHA down regulates HIF-1α protein levels independent of protein degradation” explicitly says the reduction does not occur through increased proteasomal degradation. The cited passages do not establish impaired nuclear accumulation or directly demonstrate the claimed suppression of HIF-1 transcriptional activity under hypoxia. (LLM, conf=0.90)
Experimental — accuracy not yet measuredVorinostat exerts broad suppressive effects on HIF signaling, resulting in robust reductions in HIF-1α protein abundance.
“Vorinostat (suberoylanilide hydroxamic acid), a pan-histone deacetylase (HDAC) inhibitor, exerts broad suppressive effects on HIF signaling, resulting in robust reductions in HIF-1α protein abundance [351,352].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [351]
The Results section (‘SAHA down regulates HIF-1α protein levels independent of protein degradation’; page unavailable) reports that vorinostat/SAHA reduced HIF-1α protein levels in liver cancer-derived cell lines, including under treatments that increased HIF-1α. The paper does not establish broad suppression of HIF signaling beyond its findings on HIF-1α expression, so that part of the claim is overstated. (LLM, conf=0.85)
Experimental — accuracy not yet measuredHDAC inhibitors have been shown to promote HIF-1α degradation, and translational inhibition of HIF-1α has been proposed as vorinostat's mechanism of action.
“HDAC inhibitors have been shown to promote HIF-1α degradation and, although the exact mechanism is not completely understood, translational inhibition of HIF-1α has been proposed as vorinostat's mechanism of action (Hutt et al., 2014).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Hutt et al., 2014
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“Our analysis revealed that SAHA did not alter the interaction of eIF3G with eIF3B or ribosomal protein S6 (Figure S4D) [50].”
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- [10]Boumber Y, Issa JP (2011) Epigenetics in cancer: what’s the future? Oncology (Williston Park) 25: 220–226, 228. 21548464
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Sorted by citations
Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer
Wigerup, C., Påhlman, S., & Bexell, D. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.04.009 · Cited by 687 · see citing works
“Another mechanism of HDAC inhibitor action might be via Hsp90 inhibition, as described above.”
BackgroundInfluentialThe transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy
Albadari, N. G., Deng, S., & Li, W. (2019) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2019.1613370 · Cited by 351 · see citing works
“have demonstrated that Vorinostat inhibits HIF-1α translation through Histone deacetylase 9 (HDAC9) and indirectly interferes with Eukaryotic translation initiation factor 3subunit G (eIF3G) in hepatocellular carcinoma [163].”
BackgroundPharmacologic Targeting of Hypoxia-Inducible Factors
Semenza, G. L. (2019) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010818-021637 · Cited by 288 · see citing works
Hypoxia as a driver of resistance to immunotherapy
Kopecka, J., Salaroglio, I. C., Pérez-Ruiz, E., Sarmento‐Ribeiro, A. B., Saponara, S., Rivas, J. D. L., & Riganti, C. (2021) · Drug Resistance Updates · doi:10.1016/j.drup.2021.100787 · Cited by 252 · see citing works
Qiu, G., Jin, M., Dai, J., Sun, W., Feng, J., & Jin, W. (2017) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2017.05.002 · Cited by 245 · see citing works
Noman, M. Z., Hasmim, M., Lequeux, A., Xiao, M., Duhem, C., Chouaı̈b, S., Berchem, G., & Janji, B. (2019) · Cells · doi:10.3390/cells8091083 · Cited by 215 · see citing works
“Drugs that induced HIF-1α degradation include Geldanamycin analog 17-AAG (tanespimycin) and 17-DMAG (alvespimycin) [96]; the next-generation EC154 molecule [96]; HDAC inhibitors (vorinostat, romidepsin, panobinostat, and belinostat, which might also act as inhibitors of HIF-1α translation) [97]; and the melphalan-deri…”
BackgroundHe, Z., & Zhang, S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.741305 · Cited by 205 · see citing works
“Vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase inhibitor that has been approved by the United States Food and Drug Administration (FDA) and has been demonstrated to negatively regulate the expression and function of HIF-1a through the inhibition of an eIF3G-dependent translation mechanism…”
BackgroundDevelopment of Inhibitors Targeting Hypoxia-Inducible Factor 1 and 2 for Cancer Therapy
Yu, T., Tang, B., & Sun, X. (2017) · Yonsei Medical Journal · doi:10.3349/ymj.2017.58.3.489 · Cited by 192 · see citing works
“Several clinically used HDAC inhibitors, such as vorinostat, have been demonstrated to promote the degradation of HIFα proteins, even though the exact mechanism is not clearly understood.(26,62) A novel HIF-1α inhibitor (CAS No.”
Interfering with Tumor Hypoxia for Radiotherapy Optimization
Telarović, I., Wenger, R. H., & Pruschy, M. N. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02000-x · Cited by 196 · see citing works
Hypoxia-induced alternative splicing: the 11th Hallmark of Cancer
Farina, A. R., Cappabianca, L. A., Sebastiano, M., Zelli, V., Guadagni, S., & Mackay, A. R. (2020) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-01616-9 · Cited by 131 · see citing works
“17DMAG and EC154 that promote VHL-dependent HIF-α degradation [271, 272], the HDAC inhibitor virinostat that promotes HIFα degradation [273], the small molecule PX12 that inhibits Hif-1α accumulation by targeting thioredoxin-1 [274, 275], the small molecular inhibitor LW6 that promotes VHL-dependent Hif-1α degradation…”
BackgroundQin, J., Liu, Y., Lu, Y., Liu, M., Li, M., Li, J., & Wu, L. (2017) · Scientific Reports · doi:10.1038/s41598-017-09244-8 · Cited by 121 · see citing works
Flavonoids Targeting HIF-1: Implications on Cancer Metabolism
Samec, M., Líšková, A., Koklesová, L., Meršaková, S., Strnádel, J., Kajo, K., Péč, M. J., Zhai, K., Šmejkal, K., Mirzaei, S., et al. (2021) · Cancers · doi:10.3390/cancers13010130 · Cited by 114 · see citing works
“Vorinostat (HDACi) Disruption of HIF-1α protein stabilization and accumulation [94]”
BackgroundHistone Deacetylases (HDACs) Guided Novel Therapies for T-cell lymphomas
Zhang, Q., Wang, S., Chen, J., & Yu, Z. (2019) · International Journal of Medical Sciences · doi:10.7150/ijms.30154 · Cited by 101 · see citing works
“resulted synergic cytotoxic antagonism in cutaneous T-cell lymphoma cells, which would show potential efficacy for the treatment of T-cell lymphomas [145, 146].”
BackgroundSerwetnyk, M. A., & Blagg, B. S. J. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2020.11.015 · Cited by 97 · see citing works
wang, L., Li, H., Ren, Y., Zou, S., Fang, W., Jiang, X., Li, J., Li, M., Liu, X., Yuan, X., et al. (2016) · Cell Death and Disease · doi:10.1038/cddis.2015.328 · Cited by 93 · see citing works
“HIF-1 activity by modulating its interactions and its acetylation status.(35,36) The above-reported results indicated that HDAC might be also involved in other paclitaxel-resistant mechan-”
ResultRecent Update of HDAC Inhibitors in Lymphoma
Chen, I., Sethy, B., & Liou, J. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.576391 · Cited by 86 · see citing works
“Combination of vorinostat with PI3K inhibitors or HSP90 inhibitors resulted in cytotoxic antagonism in CTCL cells, and investigation of this could be useful (Wozniak et al., 2010; Hutt et al., 2014).”
BackgroundPrieto-Dominguez, N., Méndez-Blanco, C., Carbajo‐Pescador, S., Fondevila, F., García-palomo, A., González-Gallego, J., & Mauriz, J. (2017) · OncoTarget · doi:10.18632/oncotarget.20592 · Cited by 81 · see citing works
“Accordingly, EF24, a curcumin analog, overcomes sorafenib resistance promoting the VHL-dependent HIF1α degradation [2], the histone deacetylase inhibitor vorinostat has been shown to inhibit HIF-1α translation through the eukaryotic translation initiation factor 3 subunit G (eIF3G) repression [44], and several miRNAs,”
BackgroundZhang, C., Yang, C., Feldman, M. J., Wang, H., Pang, Y., Maggio, D. M., Zhu, D., Nesvick, C. L., Dmitriev, P., Bullova, P., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.18125 · Cited by 80 · see citing works
“Even others suggest HIF translational inhibition through indirect interference with eukaryotic initiation factor-G3 (eIFG3) [34].”
BackgroundMammadzada, P., Corredoira, P. M. F., & André, H. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03422-9 · Cited by 90 · see citing works
Histone deacetylase inhibitors in hepatocellular carcinoma: A therapeutic perspective.
Tsilimigras, D., Ntanasis-Stathopoulos, I., Moris, D., Spartalis, E., & Pawlik, T. (2018) · Surgical oncology · doi:10.1016/j.suronc.2018.07.015 · Cited by 69 · see citing works
Adhikari, N., Jha, T., & Ghosh, B. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01676 · Cited by 74 · see citing works
Missiaen, R., Lesner, N. P., & Simon, M. C. (2023) · The EMBO Journal · doi:10.15252/embj.2022112067 · Cited by 74 · see citing works
“Moreover, histone deacetylase inhibitors, such as vori-nostat induce anti-hypoxic activity by degrading the HIF-1 a subunit in liver cancer-derived cells (Hutt et al , 2014).”
An Overview of the Recent Development of Anticancer Agents Targeting the HIF-1 Transcription Factor
Shirai, Y., Chow, C. C. T., Kambe, G., Suwa, T., Kobayashi, M., Takahashi, I., Harada, H., & Nam, J. (2021) · Cancers · doi:10.3390/cancers13112813 · Cited by 74 · see citing works
Inflammatory Networks in Renal Cell Carcinoma
Kruk, L., Mamtimin, M., Braun, A., Anders, H., Andrassy, J., Gudermann, T. W., & Mammadova‐Bach, E. (2023) · Cancers · doi:10.3390/cancers15082212 · Cited by 57 · see citing works
Schoepflin, Z. R., Shapiro, I. M., & Risbud, M. V. (2016) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2787 · Cited by 53 · see citing works
“This PHD2-dependent mechanism is novel and unique to cells of the NP and is substantially different from results in cancer cell lines that implicate a PHD-VHL-independent process for HIF-1a destabilization incurred by HDAC inhibition((18,19)) or repression of HIF-1a translation caused by HDAC inhibition.((20)) Use of…”
ResultGlutamine Metabolism: Molecular Regulation, Biological Functions, and Diseases
Kumar, M. A., Baba, S. K., Khan, I. R., Khan, M. S., Husain, F. M., Ahmad, S., Haris, M., Singh, M., Akil, A. A., Macha, M. A., et al. (2025) · MedComm · doi:10.1002/mco2.70120 · Cited by 49 · see citing works
The epigenetic regulation of HIF-1α by SIRT1 in MPP + treated SH-SY5Y cells
Dong, S., Guo, Y., Feng, Y., Cui, X., Kuo, S., Liu, T., & Wu, Y. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.01.013 · Cited by 49 · see citing works
“Besides hypoxia, HIF-1α can be activated by environmental stimuli under normoxic conditions [23,24].”
BackgroundEpigenetic Therapy for Solid Tumors: Highlighting the Impact of Tumor Hypoxia
Ramachandran, S., Ient, J., Göttgens, E., Krieg, A. J., & Hammond, E. M. (2015) · Genes · doi:10.3390/genes6040935 · Cited by 55 · see citing works
Epigenetic Targeting of Autophagy via HDAC Inhibition in Tumor Cells: Role of p53
Mrakovcic, M., Bohner, L. O. L., Hanisch, M. R., & Fröhlich, L. F. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19123952 · Cited by 48 · see citing works
Histone Deacetylase Inhibitor-Induced Autophagy in Tumor Cells: Implications for p53
Mrakovcic, M., Kleinheinz, J., & Fröhlich, L. F. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18091883 · Cited by 53 · see citing works
“SAHA, including several other HDACi, have been reported to have anti-angiogenic properties by decreasing the expression of several pro-angiogenic factors, including vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1a (HIF1a) which is independent of p53 [140,169].”
BackgroundHIF-1α Is a Rational Target for Future Ovarian Cancer Therapies
Wang, X., Du, Z., Xu, T., Wang, X., Li, W., Gao, J., Li, J., & Zhu, H. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.785111 · Cited by 46 · see citing works
Cox, D. J., Coleman, A. M., Gogan, K. M., Phelan, J. J., Maoldomhnaigh, C. Ó., Dunne, P. J., Basdeo, S. A., & Keane, J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01609 · Cited by 53 · see citing works
“In the context of liver cancer, SAHA has been shown to inhibit HIF-1α expression and nuclear translocation (53, 54).”
BackgroundChang, W. H., & Lai, A. G. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.05.011 · Cited by 56 · see citing works
Class I histone deacetylases regulate p53/NF-κB crosstalk in cancer cells
Schäfer, C., Göder, A., Beyer, M., Kiweler, N., Mahendrarajah, N., Rauch, A., Nikolova, T., Stojanovic, N., Wieczorek, M., Reich, T. R., et al. (2016) · Cellular Signalling · doi:10.1016/j.cellsig.2016.11.002 · Cited by 46 · see citing works
Acetazolamide potentiates the anti-tumor potential of HDACi, MS-275, in neuroblastoma
Mokhtari, R. B., Baluch, N., Tsui, M., Kumar, S., Homayouni, T. S., AITKEN, K. J., Das, B., Baruchel, S., & Yeger, H. (2017) · BMC Cancer · doi:10.1186/s12885-017-3126-7 · Cited by 45 · see citing works
“translation [42]) the combination might produce a synergistic effect by blocking the ability of tumor cells to overcome hypoxic stress induced apoptosis [8, 44, 45].”
BackgroundZhe, N., Chen, S.-Y., Zhou, Z., Liu, P., Lin, X.-J., Yu, M.-S., Cheng, B.-Q., Zhang, Y.-M., & Wang, J.-S. (2016) · Cancer Biology & Therapy · doi:10.1080/15384047.2016.1177679 · Cited by 42 · see citing works
“Hypoxia-inducible factor (HIF) is a major molecular response to hypoxia and regulates numerous processes such as angiogenesis, metabolism, and proliferation.(8) HIF proteins are composed of 2 different subunits: an oxygen-labile a subunit and a constitutively expressed b subunit.”
BackgroundIaconis, D., Monti, M., Renda, M., van Koppen, A., Tammaro, R., Chiaravalli, M., Cozzolino, F., Pignata, P., Crina, C., Pucci, P., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-01156-x · Cited by 52 · see citing works
“References for antibodies’ specificity 14, 61 : for eIF4E and eIF4A1 62 ; for eIF3G 63, 64 ; for eIF3B.”
Angelucci, A., Monache, S. D., Cortellini, A., Padova, M. D., & Ficorella, C. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19010299 · Cited by 37 · see citing works
“Vorinostat Histone deacetylase inhibitors HIF1-α 5FU No, experimental use Oral [84,85]”
BackgroundThe VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma
Song, P., Zhang, J., Tan, X., Huang, Y., Xu, J., Silk, N., Zhang, D., Liu, Q., & Jiang, J. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.586857 · Cited by 42 · see citing works
Regulation of hypoxia-inducible factor functions in the nucleus by sphingosine-1-phosphate
Hait, N. C., Maiti, A., Xu, P., Qi, Q., Kawaguchi, T., Okano, M., Takabe, K., Yan, L., & Luo, C. (2020) · The FASEB Journal · doi:10.1096/fj.201901734rr · Cited by 41 · see citing works
Eskandani, M., Vandghanooni, S., Barar, J., Nazemiyeh, H., & Omidi, Y. (2017) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2016.10.113 · Cited by 38 · see citing works
Jalouli, M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26041752 · Cited by 30 · see citing works
“Vorinostat (SAHA), an HDAC inhibitor, reduces HIF-1 α expression, thereby inhibiting autophagy in glioblastoma at concentrations of 1–10 µ M [95].”
The role of HIF in angiogenesis, lymphangiogenesis, and tumor microenvironment in urological cancers
Shen, L., Chai, Y., Zheng, X., & Xu, X. (2023) · Molecular Biology Reports · doi:10.1007/s11033-023-08931-2 · Cited by 35 · see citing works
“Hutt et al. stated that vorinostat inhibits the translation of HIF-1α and may be a potential approach in cancer treatment [ 82 ].”
ResultLi, Y.-L., Zhang, N.-Y., Hu, X., Chen, J., Rao, M., Wu, L., Li, Q.-Y., Zhang, B., Yan, W., & Zhang, C. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.03.004 · Cited by 28 · see citing works
Regulating the Expression of HIF-1α or lncRNA: Potential Directions for Cancer Therapy
Zhang, M., Zhang, Y., Ding, Y., Huang, J., Yao, J., Xie, Z., Lv, Y., & Zuo, J. (2022) · Cells · doi:10.3390/cells11182811 · Cited by 24 · see citing works
Liu, N., Liu, H., Chen, H.-R., Wang, G., Teng, H., & Chang, Y.-L. (2019) · Colloids and Surfaces B: Biointerfaces · doi:10.1016/j.colsurfb.2019.110753 · Cited by 28 · see citing works
Hypoxia in Lung Cancer Management: A Translational Approach
Ancel, J., Perotin, J., Dewolf, M., Launois, C., Mulette, P., Nawrocki‐Raby, B., Dalstein, V., Gilles, C., Deslée, G., Polette, M., et al. (2021) · Cancers · doi:10.3390/cancers13143421 · Cited by 32 · see citing works
Ferlazzo, N., Currò, M., Giunta, M. L., Longo, D., Rizzo, V., Caccamo, D., & Ientile, R. (2019) · Amino Acids · doi:10.1007/s00726-019-02759-6 · Cited by 26 · see citing works
Fakhri, S., Moradi, S. Z., Faraji, F., Kooshki, L., Webber, K. J., & Bishayee, A. (2023) · Cancer and Metastasis Reviews · doi:10.1007/s10555-023-10136-9 · Cited by 30 · see citing works
Rausch, M., Weiss, A., Zoetemelk, M., Piersma, S. R., Jiménez, C. R., B, J. R. V. B., & Nowak-Sliwinska, P. M. (2020) · Cancers · doi:10.3390/cancers12113172 · Cited by 24 · see citing works
“…the ODC influence these processes directly, as (i) panobinostat inhibits the attachment and thereby the motility of cancer cells [48,49], (ii) vorinostat blocks the translation machinery [50,51], or (iii) axitinib alters the cellular homeostasis by inducing the permeabilization of mitochondria [52].”
Zhou, W., Yang, J., Saren, G., Zhao, H., Cao, K., Fu, S., Pan, X., Zhang, H., Wang, A., & Chen, X. (2020) · Theranostics · doi:10.7150/thno.44961 · Cited by 25 · see citing works
“Recent studies found that HDAC activity triggered HIF-1α degradation and repressed HIF-1α function [55-60].”
BackgroundJoly, P., Vignaud, H., Martino, J. S. D., Ruiz, M., Garin, R., Restier, L., Belmalih, A., Marchal, C., Cullin, C., Arveiler, B., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0179369 · Cited by 27 · see citing works
Self-citationHDAC6 regulates sensitivity to cell death in response to stress and post-stress recovery
Ryu, H.-W., Won, H.-R., Lee, D. H., & Kwon, S. H. (2017) · Cell Stress and Chaperones · doi:10.1007/s12192-017-0763-3 · Cited by 30 · see citing works
Tumor Hypoxia As an Enhancer of Inflammation-Mediated Metastasis: Emerging Therapeutic Strategies
DiGiacomo, J. W., & Gilkes, D. M. (2018) · Targeted Oncology · doi:10.1007/s11523-018-0555-4 · Cited by 29 · see citing works
Wang, Y., Yi, Y.-F., Yao, J., Wan, H.-Q., Yu, M., Ge, L., Zeng, X.-B., Wu, M., & Mei, L. (2022) · Acta Biomaterialia · doi:10.1016/j.actbio.2022.09.035 · Cited by 23 · see citing works
Goto, K., Annan, D. A., Morita, T., Li, W.-W., Muroyama, R., Matsubara, Y., Ito, S., Nakagawa, R., Tanoue, Y., Jinushi, M., et al. (2016) · Scientific Reports · doi:10.1038/srep38407 · Cited by 23 · see citing works
Sadeghi, M. R., Moslehi, A., Kheiry, H., Kiani, F. K., Zarei, A., Khodakarami, A., Karpisheh, V., Masjedi, A., Rahnama, B., Hojjat‐Farsangi, M., et al. (2024) · Cancer Cell International · doi:10.1186/s12935-024-03393-3 · Cited by 22 · see citing works
“Hypoxia-Inducible Factors (HIF) are super-regulators in several processes such as angiogenesis and proliferation [14].”
BackgroundSubramanian, K., Hutt, D. M., Scott, S. M., Gupta, V. R., Mao, S., & Balch, W. E. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.010524 · Cited by 21 · see citing works
“(2020) 295(23) 8017–8035 8027 caused by chronic expression of misfolded variants of CFTR, AAT, and NPC1 (119).”
ResultInfluentialSelf-citationMartin, A. R., Ronco, C., Demange, L., & Benhida, R. (2016) · MedChemComm · doi:10.1039/c6md00432f · Cited by 25 · see citing works
Chattopadhyay, T., & Mallick, B. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.121954 · Cited by 20 · see citing works
Targeting Histone Modifications in Bone and Lung Metastatic Cancers
Edwards, C. M., & Johnson, R. W. (2021) · Current Osteoporosis Reports · doi:10.1007/s11914-021-00670-2 · Cited by 27 · see citing works
An overview of biological research on hypoxia-inducible factors (HIFs)
Liu, Z., Wu, Z., Fan, Y., & Fang, Y. (2020) · Endokrynologia Polska · doi:10.5603/ep.a2020.0064 · Cited by 26 · see citing works
“Camptothecin drugs can be used for clinical treatment of small cell lung cancer and ovarian cancer [85].”
BackgroundStochasticity of anticancer mechanisms underlying clinical effectiveness of vorinostat
Omari, N. E., Khalid, A., Makeen, H. A., Alhazmi, H. A., Albratty, M., Mohan, S., Tan, C. S., Ming, L. C., Chook, J. B., & Bouyahya, A. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e33052 · Cited by 16 · see citing works
“Indeed, in liver cancer cell lines, Hutt et al. [68] showed that vorinostat inhibits HIF-1 α expression via inhibition of translation, independent of proteasome degradation, autophagy, and p53.”
BackgroundXu, L., Wang, J., Liu, B., Fu, J., Zhao, Y., Yu, S., Shen, L., Yan, X., & Su, J. (2022) · Biomedicines · doi:10.3390/biomedicines10020374 · Cited by 17 · see citing works
“As a member of class IIa histone deacetylases, HDAC9 catalyzes the deacetylation of histones and nonhistone substrates, which regulates a variety of key cellular processes, such as the immune response [8], cell cycle [9], apoptosis [10], and angiogenesis [11].”
BackgroundMcDermott, A., & Tavassoli, A. (2024) · Transcription · doi:10.1080/21541264.2024.2417475 · Cited by 15 · see citing works
“Vorinostat has also been proposed to act through HDAC9 to inhibit HIF-1α translation, mediated via interaction with the eukaryotic translation initiation factor – eIF3G [179].”
Farina, A. R., Cappabianca, L. A., Zelli, V., Sebastiano, M., & Mackay, A. R. (2021) · World Journal of Stem Cells · doi:10.4252/wjsc.v13.i7.685 · Cited by 17 · see citing works
Minisini, M., Cricchi, E., & Brancolini, C. (2023) · Life · doi:10.3390/life14010020 · Cited by 13 · see citing works
“This mechanism is also utilized by SAHA [106].”
BackgroundMethodHypoxic microenvironment in cancer: role in metabolic reprogramming
Sureka, N., Maheshwari, R., Agravat, A., Singhal, S., Zaman, S., Rishi, B., Siraj, F., Zaheer, S., & Misra, A. (2026) · Frontiers in Oncology · doi:10.3389/fonc.2026.1771365 · Cited by 11 · see citing works
“HDACi reduce HIF output by blocking HIF transactivation and/or lowering HIF-1 a protein (often via translational control) (201 – 203), while BET inhibitors (e.g., JQ1, OTX015/MK-8628, molibresib, pelabresib) limit recruitment of BRD proteins to hypoxia-responsive promoters, diminishing expression…”
InfluentialNovel anticancer drug discovery strategies targeting hypoxia-inducible factors
Mustafa, M., Rashed, M., & Winum, J. (2024) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2024.2442739 · Cited by 11 · see citing works
“Research has also indicated that Vorinostat inhibits HIF-1α translation through HDAC9 inhibition, indirectly affecting the eukaryotic translation initiation factor 3 subunit G in HCC cells [123–125].”
Messa, L., Celegato, M., Bertagnin, C., Mercorelli, B., Nannetti, G., Palù, G., & Loregian, A. (2018) · Scientific Reports · doi:10.1038/s41598-018-24470-4 · Cited by 11
Therapeutic Strategies to Block the Hypoxic Response
DiGiacomo, J. W., & Gilkes, D. M. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-12734-3_10 · Cited by 16 · see citing works
Using Histone Deacetylase Inhibitors to Analyze the Relevance of HDACs for Translation
Hutt, D. M., Roth, D., Marchal, C., & Bouchecareilh, M. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-6527-4_6 · Cited by 13 · see citing works
Self-citation5-Azacitidine induces demethylation of PTPL1 and inhibits growth in non-Hodgkin lymphoma
Wang, W., Wang, J., Li, M., Ying, J., & Jing, H. (2015) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2015.2269 · Cited by 10
“Epigenetic abnormalities affecting histone-modifying enzymes and regulators, such as histone deacetylases (HDACs), have also been described in lymphoma (21).”
Interactions Between Non-Coding RNAs and HIF-1alpha in the Context of Colorectal Cancer
Gong, L., Zhang, H., Liu, Y., Wang, X., & Xia, R. (2025) · Biomolecules · doi:10.3390/biom15040510 · Cited by 9 · see citing works
“Additionally, the downregulation of miR-210-3p augments oxidative phosphorylation (OXPHOS).”
Moerman-Herzog, A. M., Mehdi, S. J., & Wong, H. K. (2020) · Cells · doi:10.3390/cells9091992 · Cited by 11 · see citing works
“Interestingly, in vitro acquired resistance to ricolinostat, a selective HDAC6 inhibitor, was associated with higher HDAC9 expression in a B-cell lymphoma cell line [143], and HDAC9 expression has been associated with drug resistance and poor prognosis in a variety of solid malignancies [144,145].”
BackgroundThe mechanism and potential targets of class II HDACs in angiogenesis
Hou, F., Li, D., Yu, H., & Kong, Q. (2017) · Journal of Cellular Biochemistry · doi:10.1002/jcb.26476 · Cited by 10 · see citing works
“While mToRC1 signaling pathway, as an important way for the normal development of the individual, can mediate the translation of HIF-1α via the phosphorylation of EIF4E binding protein 1 (4E-BP1), which disrupts its binding to eIF4E thereby stimulating cap-dependent translation.(60) High expression of HDAC9may increas…”
BackgroundTang, F.-B., Dai, Y.-L., Zhou, G.-Y., Zhang, W.-H., Wang, H., Li, Y., Rui-Liu, Luo, H.-M., & Hu, S. (2017) · Journal of Burn Care & Research · doi:10.1097/bcr.0000000000000568 · Cited by 9
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“Scale bar: 50 µm.”
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“2026;58(1):26-47 known histone deacetylase inhibitor capable of decreasing HIF-1 α protein expression [115] and nuclear translocation [116].”
Advances and challenges in drug repurposing in precision therapeutics of colorectal cancer
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Self-citationResistance to Inhibitors of Angiogenesis
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“Huh7 cells were purchased from ATCC and cultured in Dulbecco’s Modified Eagle Medium containing 10% (v/v) fetal bovine serum (10).”
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“In each of the aforementioned scenarios, the subsequent cascade of aberrant physiological events present in women with this disorder is partially a consequence of placental stress, and histone deacetylases (HDACs) are related to a number of these processes [34,38–40].”
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“Vorinostat, as an HDAC inhibitor, can modify chromatin modifications and restore tumor suppressor gene expression [62 ], while also influencing the expression of pro-angiogenic factors (such as VEGF and its recep - tor KDR).”
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“Vorinostat, a histone deacetylase inhibitor (HDACi), which prevents angiogenesis by inhibiting the expression of HIF-1α, a critical regulator of tumour vessel formation, is also FDA approved for cutaneous T cell lymphoma [142].”
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- Authors
- Hutt, D. M., Roth, D. M., Vignaud, H., Cullin, C., & Bouchecareilh, M.
- Affiliations
- Scripps Research Institute (US)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Bouchecareilh, Marion
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-08-28
- Volume
- 9
- Issue
- 8
- Pages
- e106224
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4148404
- OpenAlex
- W1965331098
- Cited by
- 109
- References
- 64
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 8 · 2023: 7 · 2022: 6 · 2021: 12 · 2020: 15 · 2019: 9 · 2018: 8 · 2017: 14 · 2016: 10 · 2015: 5
- FWCI
- 3.97
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Institut National de la Santé et de la Recherche Médicale (U1053)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- vorinostat, histone deacetylase inhibitors, hypoxia-inducible factor-1α, protein synthesis inhibition, eIF3h, hepatocellular carcinoma, liver cancer, tumor angiogenesis, HDAC9, cutaneous T-cell lymphoma
- MeSH terms
- Vorinostat, Histone Deacetylases, Humans, Hydroxamic Acids, Liver Neoplasms, Repressor Proteins, Protein Biosynthesis, Gene Expression Regulation, Neoplastic, Gene Silencing, Eukaryotic Initiation Factor-3, Cell Line, Tumor, Hypoxia-Inducible Factor 1, alpha Subunit, Histone Deacetylase Inhibitors
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