Pharmacological or transcriptional inhibition of both HDAC 1 and 2 leads to cell cycle blockage and apoptosis via p21Waf1/Cip1 and p19INK4d upregulation in hepatocellular carcinoma
Open accessAbstract
Abstract Objectives Histone deacetylases (HDACs) are commonly dysregulated in cancer and represent promising therapeutic targets. However, global HDAC inhibitors have shown limited efficacy in the treatment of solid tumours, including hepatocellular carcinoma (HCC). In this study, we investigated the therapeutic effect of selectively inhibiting HDAC1 and 2 in HCC. Methods HDAC1 inhibitor Tacedinaline (CI994), HDAC2 inhibitor Santacruzamate A (CAY10683), HDAC1/2 common inhibitor Romidepsin (FK228) and global HDAC inhibitor Vorinostat (SAHA) were used to treat HCC cells. Cell cycle, apoptosis and the protein levels of CDKs and CDKNs were performed to evaluate HCC cell growth. Inhibition of HDAC1/2 by RNAi was further investigated. Results Combined inhibition of HDAC1/2 led to HCC cell morphology changes, growth inhibition, cell cycle blockage and apoptosis in vitro and suppressed the growth of subcutaneous HCC xenograft tumours in vivo. p21Waf1/Cip1 and p19INK4d, which play roles in cell cycle blockage and apoptosis induction, were upregulated. Inhibition of HDAC1/2 by siRNA further demonstrated that HDAC1 and 2 cooperate in blocking the cell cycle and inducing apoptosis via p19INK4d and p21Waf1/Cip1 upregulation. Finally, H3K18, H3K56 and H4K12 in the p19INK4d and p21Waf1/Cip1 promoter regions were found to be targets of HDAC1/2. Conclusions Pharmacological or transcriptional inhibition of HDAC1/2 increases p19INK4d and p21Waf1/Cip1 expression, decreases CDK expression and arrests HCC growth. These results indicated a potential pharmacological mechanism of selective HDAC1/2 inhibitors in HCC therapy.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
HDAC inhibitors demonstrate anti-inflammatory and neuroprotective effects in neurodegenerative models by dampening inflammatory signaling and supporting synaptic and cognitive function.
“HDAC inhibitors also demonstrate anti-inflammatory and neuroprotective effects in neurodegenerative models by dampening inflammatory signaling and supporting synaptic and cognitive function (Morrison et al., 2006; Zhou et al., 2018; Kumar et al., 2022).”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Zhou et al., 2018
Cites
1 retracted
Fan, C., Pan, Y., Yang, Y., Di, S., Jiang, S., Ma, Z., Li, T. X., Zhang, Z., Li, W., Li, X., et al. (2015) · Journal of Pineal Research · doi:10.1111/jpi.12261 · Cited by 59 · see citing works
RetractedGlobal cancer statistics, 2012
Torre, L. A., Bray, F., Siegel, R. L., Ferlay, J., Lortet‐Tieulent, J., & Jemal, A. (2015) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.21262 · Cited by 26,858 · see citing works
Sorafenib in advanced hepatocellular carcinoma
Llovet, J. M., Ricci, S., Mazzaferro, V., Hilgard, P., Gane, E., Blanc, J.-F., de Oliveira, A. C., Santoro, A., Raoul, J.-L., Forner, A., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0708857 · Cited by 13,097 · see citing works
Cheng, A.-L., Kang, Y.-K., Chen, Z., Tsao, C.-J., Qin, S., Kim, J. S., Luo, R., Feng, J., Ye, S., Yang, T.-S., et al. (2009) · The Lancet Oncology · doi:10.1016/s1470-2045(08)70285-7 · Cited by 5,832 · see citing works
The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.
Wade Harper, J. (1993) · Cell · doi:10.1016/0092-8674(93)90499-g · Cited by 5,651 · see citing works
p21 is a universal inhibitor of cyclin kinases
Xiong, Y., Hannon, G., Zhang, H., Casso, D., Kobayashi, R., & Beach, D. (1993) · Nature · doi:10.1038/366701a0 · Cited by 3,691 · see citing works
Haberland, M., Montgomery, R. L., & Olson, E. N. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2485 · Cited by 2,541 · see citing works
Primary liver cancer: Worldwide incidence and trends
Bosch, F. X., Ribes, J., Díaz, M., & Clèries, R. (2004) · Gastroenterology · doi:10.1053/j.gastro.2004.09.011 · Cited by 2,473 · see citing works
Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders
Falkenberg, K. J., & Johnstone, R. W. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4360 · Cited by 1,564 · see citing works
The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men
Yang, X., & Seto, E. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2346 · Cited by 1,239 · see citing works
Yang, X.-J., & Seto, E. (2007) · Oncogene · doi:10.1038/sj.onc.1210599 · Cited by 1,040 · see citing works
Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma
Maluccio, M. A., & Covey, A. M. (2012) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.21161 · Cited by 841 · see citing works
Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma
Arzumanyan, A. L., Reis, H. M. G. P. V., & Feitelson, M. A. (2013) · Nature reviews. Cancer · doi:10.1038/nrc3449 · Cited by 801 · see citing works
(2002) · PubMed · Cited by 732 · see citing works
Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractilityPreprint
Montgomery, R. L., Davis, C. A., Potthoff, M. J., Haberland, M., Fielitz, J., Qi, X., Hill, J. A., Richardson, J. A., & Olson, E. N. (2007) · Genes & Development · doi:10.1101/gad.1563807 · Cited by 716 · see citing works
Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining
Miller, K. M., Tjeertes, J. V., Coates, J., Legube, G., Polo, S. E., Britton, S., & Jackson, S. P. (2010) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1899 · Cited by 629 · see citing works
SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation
Barber, M. F., Michishita-Kioi, E., Xi, Y., Tasselli, L., Kioi, M., Moqtaderi, Z., Tennen, R. I., Paredes, S., Young, N. L., Chen, K., et al. (2012) · Nature · doi:10.1038/nature11043 · Cited by 621 · see citing works
Advances in targeted therapies for hepatocellular carcinoma in the genomic era
Llovet, J. M., Villanueva, A., Lachenmayer, A., & Finn, R. S. (2015) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2015.103 · Cited by 619 · see citing works
(2011) · PubMed Central · Cited by 560 · see citing works
Lauffer, B. E. L., Mintzer, R., Fong, R., Mukund, S., Tam, C., Zilberleyb, I., Flicke, B., Ritscher, A., Fedorowicz, G., Vallero, R., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.490706 · Cited by 429 · see citing works
The Double Bromodomain Proteins Brd2 and Brd3 Couple Histone Acetylation to Transcription
LeRoy, G., Rickards, B., & Flint, S. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.01.018 · Cited by 374 · see citing works
Histone deacetylases 1 and 2 act in concert to promote the G1-to-S progressionPreprint
Yamaguchi, T., Cubizolles, F., Zhang, Y., Reichert, N., Kohler, H., Seiser, C., & Matthias, P. (2010) · Genes & Development · doi:10.1101/gad.552310 · Cited by 294 · see citing works
Collaborative spirit of histone deacetylases in regulating chromatin structure and gene expression
Yang, X., & Seto, E. (2003) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(03)00015-7 · Cited by 241 · see citing works
Cell Cycle and Checkpoint Regulation of Histone H3 K56 Acetylation by Hst3 and Hst4
Maas, N. L., Miller, K. M., DeFazio, L. G., & Toczyski, D. P. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.06.006 · Cited by 237 · see citing works
Shen, Y.-C., Ou, D., Hsu, C., Lin, K.-L., Chang, C.-Y., Lin, C.-Y., Liu, S., & Cheng, A.-L. (2012) · British Journal of Cancer · doi:10.1038/bjc.2012.559 · Cited by 202 · see citing works
Xie, W., Song, C., Young, N. L., Sperling, A. S., Xu, F., Sridharan, R., Conway, A. E., Garcia, B. A., Plath, K., Clark, A. T., et al. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.02.004 · Cited by 197 · see citing works
Beckers, T. L., Burkhardt, C., Wieland, H., Gimmnich, P., Ciossek, T., Maier, T. M., & Sanders, K. (2007) · International Journal of Cancer · doi:10.1002/ijc.22751 · Cited by 191 · see citing works
FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib
Gao, L., Wang, X., Tang, Y., Huang, S., Hu, C.-A. A., & Teng, Y. (2017) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-016-0478-9 · Cited by 180 · see citing works
Clinical Significance of Histone Deacetylase 1 Expression in Patients with Hepatocellular Carcinoma
Rikimaru, T., Taketomi, A., Yamashita, Y., Shirabe, K., Hamatsu, T., Shimada, M., & Maehara, Y. (2007) · Oncology · doi:10.1159/000111106 · Cited by 172 · see citing works
Witt, A. E., Lee, C.-W., Lee, T. I., Azzam, D. J., Wang, B., Caslini, C., Petrocca, F., Grosso, J., Jones, M., Cohick, E. B., et al. (2017) · Oncogene · doi:10.1038/onc.2016.337 · Cited by 172 · see citing works
Hepatocellular carcinoma: epidemiology and risk factors
Kew, M. C. (2014) · Journal of Hepatocellular Carcinoma · doi:10.2147/jhc.s44381 · Cited by 136 · see citing works
Quint, K., Agaimy, A., Fazio, P. D., Montalbano, R., Steindorf, C., Jung, R., Hellerbrand, C., Hartmann, A., Sitter, H., Neureiter, D., et al. (2011) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-011-1103-0 · Cited by 119 · see citing works
Histone deacetylase inhibitors activate INK4d gene through Sp1 site in its promoter
Yokota, T., Matsuzaki, Y., Miyazawa, K., Zindy, F., Roussel, M. F., & Sakai, T. (2004) · Oncogene · doi:10.1038/sj.onc.1207689 · Cited by 96 · see citing works
Pavlik, C. M., Wong, C. Y. B., Ononye, S. N., Lopéz, D., Engene, N., McPhail, K. L., Gerwick, W. H., & Balunas, M. J. (2013) · Journal of Natural Products · doi:10.1021/np400198r · Cited by 93 · see citing works
Noh, J. H., Bae, H. J., Eun, J. W., Shen, Q., Park, S. J., Kim, H. S., Nam, B., Shin, W. C., Lee, E. K., Lee, K., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-2109 · Cited by 62 · see citing works
Che-1 Arrests Human Colon Carcinoma Cell Proliferation by Displacing HDAC1 from the p21 Promoter
Padova, M. D., Bruno, T., Nicola, F. D., Iezzi, S., D’Angelo, C., Gallo, R., Nicosia, D., Corbi, N., Biroccio, A., Floridi, A., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m306694200 · Cited by 59 · see citing works
Damaskos, C., Garmpis, N., Karatzas, T., et al. (2015) · PubMed · Cited by 58 · see citing works
Histone deacetylase 8 is deregulated in urothelial cancer but not a target for efficient treatment
Lehmann, M., Hoffmann, M. J., Koch, A., Ulrich, S. M., Schulz, W. A., & Niegisch, G. (2014) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-014-0059-8 · Cited by 34 · see citing works
Yun, S., Lee, J., Jung, K. H., Lee, H., Lee, S., Hong, S., & Hong, S. (2013) · International Journal of Oncology · doi:10.3892/ijo.2013.1912 · Cited by 5 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Kumar, V., Kundu, S., Singh, A., & Singh, S. (2022) · Current Neuropharmacology · doi:10.2174/1570159x19666210609160017 · Cited by 210 · see citing works
HDAC2 and 7 down-regulation induces senescence in dermal fibroblasts
Warnon, C., Bouhjar, K., Ninane, N., Verhoyen, M., Fattaccioli, A., Fransolet, M., Lambert de Rouvroit, C., Poumay, Y., Piel, G., Mottet, D., et al. (2021) · Aging · doi:10.18632/aging.203304 · Cited by 25 · see citing works
Lv, L.-Z., Wang, Z.-D., Ren, J.-J., Li, L.-H., Liu, X.-B., Li, J.-L., Zhu, H., Jiang, B., Han, Y.-P., Zhou, X.-M., et al. (2026) · Frontiers in Genetics · doi:10.3389/fgene.2025.1722453 · Cited by 7 · see citing works
- Authors
- Zhou, H., Cai, Y., Liu, D., Li, M., Sha, Y., Zhang, W., Wang, K., Gong, J., Tang, N., Huang, A., & Xia, J.
- Affiliations
- Second Affiliated Hospital of Chongqing Medical University (CN)
- Chongqing Medical University (CN)
- Venue
- Cell Proliferation
- Publisher
- Wiley
- Published
- 2018-02-27
- Volume
- 51
- Issue
- 3
- Pages
- e12447-e12447
- ISSN
- 0960-7722 (ISSN-L)
- 1365-2184
- PMC
- PMC6528930
- OpenAlex
- W2794135090
- Cited by
- 85
- References
- 39
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 7 · 2023: 13 · 2022: 7 · 2021: 19 · 2020: 15 · 2019: 9 · 2018: 3
- FWCI
- 4.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cell Proliferation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81602045, 81371827, 81471946, 81572683, 81602417)
- Chongqing Medical University (CYYQ201503)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- hepatocellular carcinoma, histone deacetylase, HDAC1, HDAC2, selective HDAC inhibitors, romidepsin, vorinostat, p21, p19INK4d, cell cycle arrest, apoptosis, cyclin-dependent kinase inhibitors, histone acetylation, tumor growth inhibition, tumor xenografts
- MeSH terms
- Vorinostat, Animals, Antineoplastic Agents, Carcinoma, Hepatocellular, Humans, Hydroxamic Acids, Liver Neoplasms, Mice, Nude, Transcription, Genetic, Up-Regulation, Gene Expression Regulation, Neoplastic, Apoptosis, Xenograft Model Antitumor Assays, Depsipeptides, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p19, Histone Deacetylase 1, Histone Deacetylase 2, Histone Deacetylase Inhibitors, Hep G2 Cells, Cell Cycle Checkpoints
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
