The epigenomic consequences of HDAC6 inactivation reveal a crucial role for P300 suggesting integrated epitherapeutic strategies
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Le résumé fourni par la source
Abstract Background: Histone deacetylases (HDACs) play a pivotal role in gene regulation, DNA synthesis, and cellular metabolism, significantly influencing cancer development. Class IIb histone deacetylase 6 (HDAC6) is crucial in maintaining protein stability and regulating chromatin dynamics, with notable implications in cancer and immune responses. Despite this, the specific effects of HDAC6 inactivation on gene regulation and chromatin remodeling remain unclear due to the subtle phenotype changes following its genetic deactivation. This study delves into how inactivating HDAC6 affects the stabilization of lysine acetyltransferase P300 and the subsequent impacts on chromatin structure and function in cancer cells. Methods & Results: Using the HDAC6 inhibitor ITF3756 and CRISPR/Cas9 gene editing, we deactivated HDAC6 in various cancer cell lines. We observed profound changes in chromatin accessibility, particularly in the acetylation of histone H3 lysines 9, 14, and 27, which accumulated into introns and distal intergenic regions as determined through ATAC-seq and H3K27Ac ChIP-seq analyses. Transcriptomics, proteomics, and gene ontology analysis revealed alterations in gene function linked to cell proliferation, adhesion, migration, and apoptosis. A notable finding was the modification of P300 ubiquitination post HDAC6 inactivation, which increased P300 expression and activity, resulting in the downregulation of genes essential for cellular proliferation and survival. Conclusions: This research underscores the significant effect of HDAC6 inactivation on the chromatin landscape in cancer cells, shedding light on the crucial role of P300 in the HDAC6-mediated anticancer response. Specifically, the role of P300 stabilization in the effectiveness of an HDAC6 inhibitor suggests for a potential shift in focus from HDAC6 to its interaction with P300. This insight could contribute to developing more precise cancer treatments by targeting this specific pathway, thereby enhancing our knowledge of cancer cell behavior and offering new therapeutic perspectives.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- The epigenomic consequences of HDAC6 inactivation reveal a crucial role for P300 suggesting integrated epitherapeutic strategies
- Date Crossref
- 22/01/2024
- Éditeur
- Research Square Platform LLC
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Istituti Clinici Scientifici Maugeri pays non établi dans la noticeÉtablissement de santé
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Sapienza University of Rome National Research Council (CNR) pays non établi dans la noticeUniversité ou école supérieure
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National Research Council pays non établi dans la noticeOrganisme public
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Urology Foundation pays non établi dans la noticeOrganisation à but non lucratif
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Fondazione G.B. Bietti pays non établi dans la noticeOrganisation à but non lucratif
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Italfarmaco (Italy) pays non établi dans la noticeEntreprise
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National Academies of Sciences pays non établi dans la noticeOrganisme public
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IRCCS Mondino Foundation pays non établi dans la noticeOrganisation à but non lucratif
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IRCCS-Fondazione Bietti pays non établi dans la noticeInstitution
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Italfarmaco Group pays non établi dans la noticeInstitution
Istituti Clinici Scientifici Maugeri, National Research Council (CNR) — Sapienza University of Rome et National Research Council, avec 7 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.