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

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.

• Authors: Amal M El-Naggar, Syam Prakash Somasekharan, Yemin Wang, Hongwei Cheng, Gian Luca Negri, Melvin Pan, Xue Qi Wang, Alberto Delaidelli, Bo Rafn, Jordan Cran, Fan Zhang, Haifeng Zhang, Shane Colborne, Martin Gleave, Anna Mandinova, Nancy Kedersha, Christopher S Hughes, Didier Surdez, Olivier Delattre, Yuzhuo Wang, David G Huntsman, Gregg B Morin, Poul H Sorensen
• Journal: EMBO reports (EMBO Rep) Vol. 20 Issue 12 Pg. e48375 (12 05 2019) ISSN: 1469-3178 [Electronic] England
• PMID: 31668005 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• Antineoplastic Agents
• Benzamides
• Hif1a protein, mouse
• Histone Deacetylase Inhibitors
• Hypoxia-Inducible Factor 1, alpha Subunit
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Pyridines
• Transcription Factors
• YB-1 protein, mouse
• entinostat

Topics

• Acetylation
• Animals
• Antineoplastic Agents (therapeutic use)
• Benzamides (therapeutic use)
• Bone Neoplasms (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cells, Cultured
• Histone Deacetylase Inhibitors (therapeutic use)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Mice
• NF-E2-Related Factor 2 (metabolism)
• Neoplasm Metastasis
• Oxidative Stress
• Pyridines (therapeutic use)
• Sarcoma, Ewing (drug therapy, metabolism, pathology)
• Transcription Factors (metabolism)