CREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas
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Abstract
Somatic mutations in CREBBP occur frequently in B-cell lymphoma. Here, we show that loss of CREBBP facilitates the development of germinal center (GC)-derived lymphomas in mice. In both human and murine lymphomas, CREBBP loss-of-function resulted in focal depletion of enhancer H3K27 acetylation and aberrant transcriptional silencing of genes that regulate B-cell signaling and immune responses, including class II MHC. Mechanistically, CREBBP-regulated enhancers are counter-regulated by the BCL6 transcriptional repressor in a complex with SMRT and HDAC3, which we found to bind extensively to MHC class II loci. HDAC3 loss-of-function rescued repression of these enhancers and corresponding genes, including MHC class II, and more profoundly suppressed CREBBP-mutant lymphomas in vitro and in vivo Hence, CREBBP loss-of-function contributes to lymphomagenesis by enabling unopposed suppression of enhancers by BCL6/SMRT/HDAC3 complexes, suggesting HDAC3-targeted therapy as a precision approach for CREBBP-mutant lymphomas. SIGNIFICANCE: Our findings establish the tumor suppressor function of CREBBP in GC lymphomas in which CREBBP mutations disable acetylation and result in unopposed deacetylation by BCL6/SMRT/HDAC3 complexes at enhancers of B-cell signaling and immune response genes. Hence, inhibition of HDAC3 can restore the enhancer histone acetylation and may serve as a targeted therapy for CREBBP-mutant lymphomas. Cancer Discov; 7(1); 38-53. ©2016 AACR.See related commentary by Höpken, p. 14This article is highlighted in the In This Issue feature, p. 1.
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These CREBBP lymphomas strictly rely on HDAC3 to reduce H3K27ac signals.
“These CREBBP lymphomas strictly rely on HDAC3 to reduce H3K27ac signals.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Jiang et al., 2017
HDAC3 is recruited to critical enhancers via the BCL6/NCOR2 complex to promote lymphomagenesis.
“HDAC3 is recruited to critical enhancers via the BCL6/NCOR2 complex to promote lymphomagenesis (Jiang et al., 2017).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Jiang et al., 2017
CREBBP silencing in murine and human cells triggers depletion of H3K27ac marks at enhancers and gene expression changes similar to human lymphomas with CREBBP mutations.
“CREBBP silencing in murine and human cells triggers the depletion of H3K27ac marks at enhancers and changes in gene expression that are very similar to signatures characterizing human lymphomas with CREBBP mutations.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Jiang et al., 2017
The BCL6-HDAC3 axis is an important oncogenic element in B-cell lymphomas characterized by CREBBP mutations.
“The role of the BCL6-HDAC3 axis as an important oncogenic element has been observed in B-cell lymphomas characterized by CREBBP mutations (Jiang et al., 2017).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Jiang et al., 2017
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“The detailed procedures of gene selection, library construction, and filtering are shown in the supplementary material and have been described previously (29, 45, 47).”
BackgroundMethodInfluentialTargeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition
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- Authors
- Jiang, Y., Ortega-Molina, A., Geng, H., Ying, H.-Y., Hatzi, K., Parsa, S., McNally, D., Wang, L., Doane, A. S., Agirre, X., Teater, M., Meydan, C., Li, Z., Poloway, D., Wang, S., Ennishi, D., Scott, D. W., Stengel, K. R., Kranz, J. E., Holson, E., Sharma, S., Young, J. W., Chu, C.-S., Roeder, R. G., Shaknovich, R., Hiebert, S. W., Gascoyne, R. D., Tam, W., Elemento, O., Wendel, H.-G., & Melnick, A. M.
- Affiliations
- Weill Cornell Medicine (US)
- Memorial Sloan Kettering Cancer Center (US)
- University of California, San Francisco (US)
- BC Cancer Agency (CA)
- Vanderbilt University (US)
- 8KDAc Therapeutics, Cambridge, Massachusetts.
- Rockefeller University (US)
- Cancer Genetics (United States) (US)
- ORCID
- Jiang, Yanwen
- Ortega-Molina, Ana
- Geng, Huimin
- Hatzi, Katerina
- Parsa, Sara
- McNally, Dylan
- Wang, Ling
- Doane, Ashley S.
- Agirre, Xabier
- Teater, Matt
- Meydan, Cem
- Li, Zhuoning
- Wang, Shenqiu
- Ennishi, Daisuke
- Scott, David W.
- Stengel, Kristy R.
- Kranz, Janice E.
- Holson, Edward
- Young, James W.
- Roeder, Robert G.
- Shaknovich, Rita
- Hiebert, Scott W.
- Gascoyne, Randy D.
- Tam, Wayne
- Elemento, Olivier
- Wendel, Hans-Guido
- Melnick, Ari M.
- Venue
- Cancer Discovery
- Published
- 2017-01-01
- Volume
- 7
- Issue
- 1
- Pages
- 38-53
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC5300005
- OpenAlex
- W2531449940
- Cited by
- 278
- References
- 42
- Citations by year
- 2026: 19 · 2025: 14 · 2024: 30 · 2023: 38 · 2022: 23 · 2021: 38 · 2020: 41 · 2019: 28 · 2018: 28 · 2017: 19
- FWCI
- 22.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (P01CA023766, R01CA194547, R01CA190384, P50CA192937, R01CA164605, R01CA187109, R01CA178765, R01CA183876, P30CA008748, T32CA009582)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Keywords
- CREB-binding protein, B-cell lymphoma, germinal center lymphoma, HDAC3, BCL6, SMRT, histone deacetylation, MHC class II, transcriptional repression, tumor suppressor function, enhancer regulation
- MeSH terms
- Histone Deacetylase 3, Acetylation, Animals, Enhancer Elements, Genetic, Histone Deacetylases, Histones, Humans, Mutation, Neoplasm Transplantation, Transcription, Genetic, Lymphoma, Large B-Cell, Diffuse, Germinal Center, Cell Line, Tumor, CREB-Binding Protein, Mice, Proto-Oncogene Proteins c-bcl-6, Gene Knockout Techniques, Nuclear Receptor Co-Repressor 2
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