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EMBO Rep. 2019 Oct 31:e48375. doi: 10.15252/embr.201948375. [Epub ahead of print]

Class I HDAC inhibitors enhance YB-1 acetylation and oxidative stress to block sarcoma metastasis.

Author information

1
Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
2
Department of Molecular Oncology, BC Cancer, part of the Provincial Health Services Authority, Vancouver, BC, Canada.
3
Department of Pathology, Faculty of Medicine, Menoufia University, Shibin El Kom, Egypt.
4
Vancouver Prostate Centre, Vancouver, BC, Canada.
5
Michael Smith Genome Sciences Centre, Vancouver, BC, Canada.
6
Brigham and Women's Hospital, Harvard University, Boston, MA, USA.
7
Massachusetts General Hospital, Harvard University, Boston, MA, USA.
8
Centre de recherche de l'Institut Curie, Paris, France.

Abstract

Outcomes for metastatic Ewing sarcoma and osteosarcoma are dismal and have not changed for decades. Oxidative stress attenuates melanoma metastasis, and melanoma cells must reduce oxidative stress to metastasize. We explored this in sarcomas by screening for oxidative stress sensitizers, which identified the class I HDAC inhibitor MS-275 as enhancing vulnerability to reactive oxygen species (ROS) in sarcoma cells. Mechanistically, MS-275 inhibits YB-1 deacetylation, decreasing its binding to 5'-UTRs of NFE2L2 encoding the antioxidant factor NRF2, thereby reducing NFE2L2 translation and synthesis of NRF2 to increase cellular ROS. By global acetylomics, MS-275 promotes rapid acetylation of the YB-1 RNA-binding protein at lysine-81, blocking binding and translational activation of NFE2L2, as well as known YB-1 mRNA targets, HIF1A, and the stress granule nucleator, G3BP1. MS-275 dramatically reduces sarcoma metastasis in vivo, but an MS-275-resistant YB-1K81-to-alanine mutant restores metastatic capacity and NRF2, HIF1α, and G3BP1 synthesis in MS-275-treated mice. These studies describe a novel function for MS-275 through enhanced YB-1 acetylation, thus inhibiting YB-1 translational control of key cytoprotective factors and its pro-metastatic activity.

KEYWORDS:

HDAC inhibitors; NRF2; YB-1; metastasis; sarcoma

PMID:
31668005
DOI:
10.15252/embr.201948375

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