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Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical models of SHH Medulloblastoma
Open accessAbstract
SHH Medulloblastoma (SHH-MB) is a pediatric brain tumor characterized by an inappropriate activation of the developmental Hedgehog (Hh) signaling. SHH-MB patients treated with the FDA-approved vismodegib, an Hh inhibitor that targets the transmembrane activator Smoothened (Smo), have shown the rapid development of drug resistance and tumor relapse due to novel Smo mutations. Moreover, a subset of patients did not respond to vismodegib because mutations were localized downstream of Smo. Thus, targeting downstream Hh components is now considered a preferable approach. We show here that selective inhibition of the downstream Hh effectors HDAC1 and HDAC2 robustly counteracts SHH-MB growth in mouse models. These two deacetylases are upregulated in tumor and their knockdown inhibits Hh signaling and decreases tumor growth. We demonstrate that mocetinostat (MGCD0103), a selective HDAC1/HDAC2 inhibitor, is a potent Hh inhibitor and that its effect is linked to Gli1 acetylation at K518. Of note, we demonstrate that administration of mocetinostat to mouse models of SHH-MB drastically reduces tumor growth, by reducing proliferation and increasing apoptosis of tumor cells and prolongs mouse survival rate. Collectively, these data demonstrate the preclinical efficacy of targeting the downstream HDAC1/2-Gli1 acetylation in the treatment of SHH-MB.
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Combination of SALL4 genetic depletion and MGCD0103 treatment does not further inhibit SHH-MB cell proliferative capability compared to either treatment alone.
“while SALL4 genetic depletion or MGCD0103 treatment alone restrains tumor cell proliferation, their combination does not further induce the inhibition of SHH-MB cells proliferative capability”
From SALL4 is a CRL3REN/KCTD11 substrate that drives Sonic Hedgehog-dependent medulloblastoma (2024) · cites this paper as [45]
The Results section on pharmacological blockade of HDAC1/2 reports that MGCD0103 alone significantly reduced proliferation in Med1-MB cells (page unavailable). Our copy does not report SALL4 depletion or compare its combination with MGCD0103 against either treatment alone; searches for SALL4 and combined knockdown did not establish that part of the claim. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe effect of mocetinostat on SHH-MB growth is linked to GLI1 acetylation.
“Interestingly mocetinostat, a selective inhibitor of HDAC1 and HDAC2, drastically reduces SHH-MB growth in mouse models, an effect linked to GLI1 acetylation [45], thereby suggesting the potential of mocetinostat to counteract, at the same time, SALL4 activity.”
From SALL4 is a CRL3REN/KCTD11 substrate that drives Sonic Hedgehog-dependent medulloblastoma (2024) · cites this paper as [45]
Mocetinostat, a selective inhibitor of HDAC1 and HDAC2, drastically reduces SHH-MB growth in mouse models.
“Interestingly mocetinostat, a selective inhibitor of HDAC1 and HDAC2, drastically reduces SHH-MB growth in mouse models, an effect linked to GLI1 acetylation [45], thereby suggesting the potential of mocetinostat to counteract, at the same time, SALL4 activity.”
From SALL4 is a CRL3REN/KCTD11 substrate that drives Sonic Hedgehog-dependent medulloblastoma (2024) · cites this paper as [45]
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SALL4 is a CRL3REN/KCTD11 substrate that drives Sonic Hedgehog-dependent medulloblastoma
Lospinoso Severini, L., Loricchio, E., Navacci, S., Basili, I., Alfonsi, R., Bernardi, F., Moretti, M., Conenna, M., Cucinotta, A., Coni, S., et al. (2024) · Cell Death & Differentiation · doi:10.1038/s41418-023-01246-6 · Cited by 13
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Metadata
- Authors
- Coni, S., Mancuso, A. B., Di Magno, L., Sdruscia, G., Manni, S., Serrao, S. M., Rotili, D., Spiombi, E., Bufalieri, F., Petroni, M., Kusio-Kobialka, M., De Smaele, E., Ferretti, E., Capalbo, C., Mai, A., Niewiadomski, P., Screpanti, I., Di Marcotullio, L., & Canettieri, G.
- Affiliations
- Sapienza University of Rome (IT)
- Italian Institute of Technology (IT)
- Istituto Neurologico Mediterraneo (IT)
- Corresponding author
- Canettieri, Gianluca
- ORCID
- Venue
- Scientific Reports
- Published
- 2017-03-09
- Volume
- 7
- Issue
- 1
- Pages
- 44079-44079
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5343431
- OpenAlex
- W2594204984
- Cited by
- 75
- References
- 1
- Citations by year
- 2026: 3 · 2025: 7 · 2023: 6 · 2022: 9 · 2021: 7 · 2020: 18 · 2019: 14 · 2018: 7 · 2017: 4
- FWCI
- 4.81
- Type
- journal article
- Language
- en
- Update notices
- correction (2017-04-21)
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, other-oa)
- Archive of Doctoral Theses and Digital Collections (University of Calabria) (submittedVersion)
- Iris (Roma Tre University) (submittedVersion)
- Funders
- Ministero dell’Istruzione, dell’Università e della Ricerca (2012CTAYSY, 20152TE5PK, PRIN(2016), PRIN2012)
- Associazione Italiana per la Ricerca sul Cancro (17575, IG17575, PRIN 2012, IG#14723)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Keywords
- SHH medulloblastoma, Hedgehog signaling, mocetinostat, pediatric brain tumors, tumor growth inhibition, apoptosis, histone deacetylase inhibitors
- MeSH terms
- Zinc Finger Protein GLI1, Animals, Medulloblastoma, Mice, Transgenic, Neoplasms, Experimental, Tumor Suppressor Proteins, Cell Line, Tumor, Mice, Histone Deacetylase 1, Histone Deacetylase 2
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