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Class I HDAC inhibitors enhance YB ‐1 acetylation and oxidative stress to block sarcoma metastasis
Author(s) -
ElNaggar Amal M,
Somasekharan Syam Prakash,
Wang Yemin,
Cheng Hongwei,
Negri Gian Luca,
Pan Melvin,
Wang Xue Qi,
Delaidelli Alberto,
Rafn Bo,
Cran Jordan,
Zhang Fan,
Zhang Haifeng,
Colborne Shane,
Gleave Martin,
Mandinova Anna,
Kedersha Nancy,
Hughes Christopher S,
Surdez Didier,
Delattre Olivier,
Wang Yuzhuo,
Huntsman David G,
Morin Gregg B,
Sorensen Poul H
Publication year - 2019
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201948375
Subject(s) - oxidative stress , metastasis , acetylation , cancer research , chemistry , biology , cancer , biochemistry , gene , genetics
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′‐ UTR s of NFE 2L2 encoding the antioxidant factor NRF 2, thereby reducing NFE 2L2 translation and synthesis of NRF 2 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 NFE 2L2 , as well as known YB ‐1 mRNA targets, HIF 1A, and the stress granule nucleator, G3 BP 1 . MS ‐275 dramatically reduces sarcoma metastasis in vivo , but an MS ‐275‐resistant YB ‐1K81‐to‐alanine mutant restores metastatic capacity and NRF 2, HIF 1α, and G3 BP 1 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.