P300/CBP acetyltransferase inhibition and degradation disrupt oncogenic transcriptional programs and reveal epigenetic vulnerabilities in multiple myeloma
Notice bibliographique
Résumé
Abstract Background: The histone acetyltransferases (HATs) P300 and CBP are critical transcriptional co-activators that regulate gene expression by catalyzing lysine acetylation on histones and non-histone substrates. These co-activators are essential for maintaining oncogenic transcriptional programs in multiple myeloma (MM), particularly those driven by IRF4 and MYC. Inobrodib (CCS1477), a selective P300/CBP bromodomain inhibitor, has shown promising early clinical activity in relapsed/refractory MM, highlighting the therapeutic relevance of this axis. However, the effects of more direct P300/CBP targeting—via catalytic inhibition or protein degradation—on chromatin structure and MM lineage survival programs remain incompletely defined. Aims: We aimed to characterize the transcriptional and epigenetic effects of catalytic inhibition and targeted degradation of P300/CBP in MM, identify determinants of resistance and sensitivity, and explore rational epigenetic drug combinations. Methods: MM cell lines were treated with selective small-molecule P300/CBP catalytic inhibitors (A-485, A-241), the bromodomain inhibitor GNE-781, the P300/CBP degrader dCBP-1, the HDAC3 inhibitor RGFP966, and the KDM6 demethylase inhibitor GSK-J4. Selected compounds were also evaluated in primary patient samples and mouse xenograft models. Mechanisms of resistance and sensitivity were elucidated using comprehensive multi-omics approaches, including RNA-Seq, ChIP-Seq, ATAC-Seq, NOME-Seq, Hi-C, and genome-wide CRISPR/Cas9 screening. Results: Catalytic inhibition of P300/CBP using A-485 or A-241 induced potent apoptotic and anti-proliferative effects across a panel of genetically diverse MM cell lines. Transcriptional profiling revealed robust preferential suppression of oncogenic transcriptional networks driven by MYC and IRF4, consistent across cell lines and primary MM samples. In MM1.S xenografts, A-485 significantly improved overall survival. Catalytic P300/CBP inhibition caused genome-wide histone deacetylation, preferentially at enhancers. Surprisingly, ATAC-Seq and in situ Hi-C showed minimal changes in chromatin accessibility and 3D genome organization, indicating that histone acetylation is not strictly required to maintain open chromatin. The P300/CBP degrader dCBP-1 induced rapid and near-complete protein degradation at nanomolar concentrations, resulting in enhanced apoptotic responses across MM cell lines. Compared to catalytic or bromodomain inhibitors, dCBP-1 elicited more profound H3K27ac loss and repressed a subset of MM-defining genes—such as TNFRSF17 (BCMA) and SLAMF7—that remained transcriptionally active following A-485 or A-241 treatment. A genome-wide CRISPR/Cas9 resistance screen identified the nuclear receptor co-repressor (NCOR1) complex containing HDAC3, which co-localizes with P300/CBP at active chromatin, as a key determinant of sensitivity to P300/CBP inhibition. NCOR1 or HDAC3 loss maintained histone acetylation and transcriptional output in the presence of A-485. These findings support a model in which loss of deacetylase activity mitigates the effects of P300/CBP blockade by reducing the turnover of acetyl marks to restore expression of oncogenic transcription factors. While the effects of short A-485 exposure were highly reversible, sustained P300/CBP inhibition and H3K27 hypoacetylation resulted in stable H3K27me3 deposition and chromatin condensation, associated with cellular commitment to die. Genetic depletion of the H3K27 demethylase KDM6A (UTX) enhanced sensitivity to P300/CBP inhibition. Pharmacological co-inhibition of P300/CBP and KDM6A using A-485 and GSK-J4 synergistically enhanced MYC/IRF4 repression and cytotoxicity in MM cell lines and patient samples, underscoring the therapeutic potential of targeting histone acetylation-methylation equilibrium. Conclusion: Collectively, these findings establish P300/CBP as a critical epigenetic dependency in MM, essential for maintaining enhancer integrity and oncogenic transcriptional networks. Both catalytic inhibition and targeted degradation of P300/CBP selectively disrupt MYC and IRF4 signaling, triggering apoptosis without inducing global transcriptional shutdown. Co-targeting the H3K27 methylation axis via KDM6A inhibition further amplifies therapeutic responses, uncovering a mechanistically rational epigenetic combination strategy. These preclinical data provide compelling justification for further development of P300/CBP-targeting agents for the treatment of MM.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».