Targeting p300/CBP axis in lethal prostate cancer
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ABSTRACT:
PROVIDER: PRJNA682218 | ENA |
REPOSITORIES: ENA
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Project description:The acetyltransferases CBP and p300 are multifunctional transcriptional co-activators; however, their acetylation targets, site-specific acetylation kinetics, and function in proteome regulation are incompletely understood. We combined quantitative proteomics with novel CBP/p300-specific catalytic inhibitors, bromodomain inhibitor, and gene knockout to show that CBP/p300 acetylates thousands of sites, including signature histone sites, as well as a multitude of sites on signaling effectors and enhancer-associated transcriptional regulators. Kinetic analysis identified a subset of CBP/p300-regulated sites with very rapid (<30min) acetylation turnover, revealing a dynamic balance between acetylation and deacetylation. Quantification of acetylation, mRNA, and protein abundance after CBP/p300 inhibition reveals a kinetically competent network of gene expression that strictly depends on CBP/p300-catalyzed rapid acetylation. Collectively, our in-depth acetylome analyses reveal systems attributes of CBP/p300 targets, and the resource dataset provides a framework for investigating CBP/p300 functions, as well as for understanding the impact of small molecule inhibitors targeting its catalytic and bromodomain activities.
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Project description:Dysregulated gene expression is one of the most prevalent features in human cancers. Here, we show that most subtypes of acute myeloid leukemia (AML) depend on the aberrant assembly of the MYB transcriptional co-activator complex. By rapid and selective peptidomimetic interference with the binding of CBP/P300 to MYB, but not CREB or MLL1, we find that the leukemic functions of MYB are mediated by CBP/P300-mediated co-activation of a distinct set of transcriptional factor complexes that are aberrantly assembled with MYB in AML cells. This therapeutic remodeling is accompanied by dynamic redistribution of CBP/P300 complexes to genes that control cellular differentiation and growth. Thus, aberrantly organized transcription factor complexes control convergent gene expression programs in AML cells. These findings establish a compelling strategy for pharmacologic reprogramming of oncogenic gene expression that supports its targeting for leukemias and other human cancers caused by dysregulated gene control.
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Project description:SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex, is the causative gene of pediatric and juvenile cancers such as rhabdoid tumors and epithelioid sarcomas. Here, we used a dual siRNA screening method based on the “simultaneous inhibition of a paralog pair” concept to identify a paralog pair comprising acetyltransferases CBP and p300 as a synthetic lethal target in SMARCB1-deficient cancers. Treatment with CBP/p300 dual inhibitors suppressed growth of cell lines and tumor xenografts derived from SMARCB1-deficient cells but not SMARCB1-proficient cells. SMARCB1-containing SWI/SNF complexes localized with H3K27me3 (a marker of transcriptional repression) and its methyltransferase, EZH2, at the promotor region of the KREMEN2 locus. By contrast, SMARCB1 deficiency led to localization of H3K27ac (a marker of transcriptional promotion) and recruitment of its acetyltransferases CBP and p300 at the KREMEN2 locus, resulting in transcriptional upregulation of KREMEN2, which cooperates with the SMARCA1 chromatin remodeling complex instead of SMARCB1-deficient residual SWI/SNF complexes. Simultaneous inhibition of CBP/p300 led to transcriptional downregulation of KREMEN2 and then induced apoptosis by monomerization of KREMEN1 due to a failure to interact with KREMEN2, which suppressing anti-apoptotic signaling pathways. Taken together, our findings indicate that simultaneous inhibitors of CBP/p300 could be promising therapeutic agents for SMARCB1-deficient cancers.
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Project description:Reversible epsilon-amino acetylation of lysine residues regulates transcription as well as metabolic flux; however, roles for specific lysine acetyltransferases in skeletal muscle physiology and function remain enigmatic. In this study, we investigated the role of the homologous acetyltransferases p300 and CBP in skeletal muscle transcriptional homeostasis and physiology in adult mice. Mice with skeletal muscle-specific and inducible knockout of p300 and/or CBP were generated by crossing mice with a tamoxifen-inducible Cre recombinase expressed under the human alpha-skeletal actin (HSA) promoter with mice harboring LoxP sites flanking exon 9 of both the Ep300 and Crebbp genes. Knockout was induced at 13-15 weeks of age via oral gavage of tamoxifen. We demonstrate that loss of both p300 and CBP in adult mouse skeletal muscle severely impairs contractile function and results in lethality within one week – a phenotype that is reversed by the presence of a single allele of either p300 or CBP. The loss of muscle function in p300/CBP double knockout mice is paralleled by substantial transcriptional alterations in gene networks central to skeletal muscle contraction and structural integrity. Changes in protein expression patterns, determined by 10-plex TMT labeling, were linked to impaired muscle function also manifest within days (WT mice were compared to day 3 and day 5 knock out mice). Together, these data reveal the requirement of p300 and CBP for the control and maintenance of contractile function and transcriptional homeostasis in skeletal muscle, and ultimately, organism survival. By extension, modulating p300/CBP function holds promise for the treatment of disorders characterized by impaired contractile function in humans.
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