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Proteasome Inhibitors Silence Oncogenes in Multiple Myeloma through Localized Histone Deacetylase 3 (HDAC3) Stabilization and Chromatin Condensation.
Maneix, Laure; Iakova, Polina; Moree, Shannon E; Hsu, Joanne I; Mistry, Ragini M; Stossi, Fabio; Lulla, Premal; Sun, Zheng; Sahin, Ergun; Yellapragada, Sarvari V; Catic, André.
Afiliación
  • Maneix L; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
  • Iakova P; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • Moree SE; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
  • Hsu JI; Cell and Gene Therapy Program at the Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • Mistry RM; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
  • Stossi F; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • Lulla P; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
  • Sun Z; Cell and Gene Therapy Program at the Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • Sahin E; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
  • Yellapragada SV; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • Catic A; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Cancer Res Commun ; 2(12): 1693-1710, 2022 12.
Article en En | MEDLINE | ID: mdl-36846090
Proteasome inhibitors have become the standard of care for multiple myeloma (MM). Blocking protein degradation particularly perturbs the homeostasis of short-lived polypeptides such as transcription factors and epigenetic regulators. To determine how proteasome inhibitors directly impact gene regulation, we performed an integrative genomics study in MM cells. We discovered that proteasome inhibitors reduce the turnover of DNA-associated proteins and repress genes necessary for proliferation through epigenetic silencing. Specifically, proteasome inhibition results in the localized accumulation of histone deacetylase 3 (HDAC3) at defined genomic sites, which reduces H3K27 acetylation and increases chromatin condensation. The loss of active chromatin at super-enhancers critical for MM, including the super-enhancer controlling the proto-oncogene c-MYC, reduces metabolic activity and cancer cell growth. Epigenetic silencing is attenuated by HDAC3 depletion, suggesting a tumor-suppressive element of this deacetylase in the context of proteasome inhibition. In the absence of treatment, HDAC3 is continuously removed from DNA by the ubiquitin ligase SIAH2. Overexpression of SIAH2 increases H3K27 acetylation at c-MYC-controlled genes, increases metabolic output, and accelerates cancer cell proliferation. Our studies indicate a novel therapeutic function of proteasome inhibitors in MM by reshaping the epigenetic landscape in an HDAC3-dependent manner. As a result, blocking the proteasome effectively antagonizes c-MYC and the genes controlled by this proto-oncogene.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Cromatina / Mieloma Múltiple Límite: Humans Idioma: En Revista: Cancer Res Commun Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Cromatina / Mieloma Múltiple Límite: Humans Idioma: En Revista: Cancer Res Commun Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos